Drug Information

General Information of This Drug

Drug ID	DRG00065
Drug Name	Irinotecan
Synonyms	irinotecan; 97682-44-5; (+)-Irinotecan; Camptosar; Irinophore C; Irinotecanum; Biotecan; Irinotecan lactone; Irinotecan mylan; Irinotecanum [INN-Latin]; Campto; Irinotecan Free base; CPT-11; (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl [1,4'-bipiperidine]-1'-carboxylate; HSDB 7607; Irinotecan (INN); NSC-728073; CHEBI:80630; CHEMBL481; UNII-7673326042; DTXSID1041051; 97682-44-5 (Free base); NSC728073; NSC 728073; (4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3',4':6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL 1,4'-BIPIPERIDINE-1'-CARBOXYLATE; 1,4'-Bipiperidine-1'-carboxylic acid (S)-4,11-diethyl-3,4,12,14- tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl ester; IRINOTECAN [INN]; Irinotecanum (INN-Latin); Irinotecan [INN:BAN]; (1,4'-Bipiperidine)-1'-carboxylic acid, 4,11-diethyl-3,4,12-14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl ester, (S)-; CPT-11 hydrochloride;Camptothecin 11 hydrochloride; Irrinotecan; Biotecan (TN); (1,4'-Bipiperidine)-1'-carboxylic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl ester; [1,4'-Bipiperidine]-1'-carboxylic acid, (4S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl ester; 1,4'-bipiperidine-1'-carboxylic acid (s)-4,11-diethyl-3,4,12,14- tetrahydro-4-hydroxy-3,14-dioxo-1h-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl ester; Irinotecan?; MFCD00866307; (4S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl (1,4'-bipiperidine)-1'-carboxylate; (4S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl [1,4'-bipiperidine]-1'-carboxylate; IRINOTECAN [MI]; IRINOTECAN [HSDB]; IRINOTECAN [VANDF]; SCHEMBL4034; IRINOTECAN [WHO-DD]; IRINOTECAN; CPT-11; BSPBio_002346; GTPL6823; DTXCID9021051; AMY4227; L01XX19; 1u65; BCP02860; BDBM50128267; s1198; AKOS015894969; AB07527; AC-7469; BCP9000793; CS-1138; DB00762; NCGC00178697-02; NCGC00178697-05; (4S)-4,11-Diethyl-4-hydroxy-3,14-dioxo-4,12-dihydro-1H-pyrano[3,4-f]quinolino[2,3-a]indolizin-9-yl 4-piperidylpiperidinecarboxylate; AS-14323; HY-16562; NCI60_005051; NS00004943; D08086; EN300-708800; AB00698464-07; AB00698464-09; AB00698464-10; AB00698464-11; AB00698464_12; AB00698464_13; AB00698464_14; A845740; Q412197; BRD-K08547377-003-02-4; (diethyl-hydroxy-dioxo-[?]yl) 4-(1-piperidyl)piperidine-1-carboxylate; (+)-7-ethyl-10-hydroxycamptothecine 10-(1,4'-bipiperidine)-1'-carboxylate; 2-methoxy-5-[2-(3-sulfophenyl)-5-(4-sulfophenyl)pyrylium-4-yl]benzenesulfonic acid; (+)-(4S)-4,11-diethyl-4-hydroxy-9-((4-piperidino-piperidino)carbonyloxy)-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinol-3,14,(4H,12H)-dione; (1,4'-bipiperidine)-1'-carboxylic acid (S)-4,11-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1H-pyrano(3',4':6,7)indolizino(1,2-b)quinolin-9-yl ester; (19S)-10,19-Diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0[2,11].0[4,9].0[15,20]]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate; (19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-7-yl [1,4'-bipiperidine]-1'-carboxylate; (19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.0^{2,11}.0^{4,9}.0^{15,20}]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-7-yl 4-(piperidin-1-yl)piperidine-1-carboxylate; (4S)-4,11-DIETHYL-4-HYDROXY-3,14-DIOXO-3,4,12,14-TETRAHYDRO-1H-PYRANO[3'',4'':6,7]INDOLIZINO[1,2-B]QUINOLIN-9-YL 1,4''-BIPIPERIDINE-1''-CARBOXYLATE; (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano[3',4':6,7]indolizino[1,2-b]quinolin-9-yl[1,4'-bipiperidine]-1'-carboxylate; [(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl] 4-piperidin-1-ylpiperidine-1-carboxylate; [1,4'']bipiperidinyl-1''-carboxylic acid (S)-4,11-diethyl-4-hydroxy-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-9-yl ester; [1,4'']Bipiperidinyl-1''-carboxylic acid 4,11-diethyl-4-hydroxy-3,13-dioxo-3,4,12,13-tetrahydro-1H-2-oxa-6,12a-diaza-dibenzo[b,h]fluoren-9-yl ester Click to Show/Hide
Target(s)	DNA topoisomerase 1 (TOP1)		Target Info
Structure
Structure	3D MOL	2D MOL
Formula	C33H38N4O6
#Ro5 Violations (Lipinski): 1	Molecular Weight (mw)	586.7
	Lipid-water partition coefficient (xlogp)	3
	Hydrogen Bond Donor Count (hbonddonor)	1
	Hydrogen Bond Acceptor Count (hbondacc)	8
	Rotatable Bond Count (rotbonds)	5
PubChem CID	60838
Canonical smiles	CCC1=C2CN3C(=CC4=C(C3=O)COC(=O)C4(CC)O)C2=NC5=C1C=C(C=C5)OC(=O)N6CCC(CC6)N7CCCCC7
InChI	InChI=1S/C33H38N4O6/c1-3-22-23-16-21(43-32(40)36-14-10-20(11-15-36)35-12-6-5-7-13-35)8-9-27(23)34-29-24(22)18-37-28(29)17-26-25(30(37)38)19-42-31(39)33(26,41)4-2/h8-9,16-17,20,41H,3-7,10-15,18-19H2,1-2H3/t33-/m0/s1
InChIKey	UWKQSNNFCGGAFS-XIFFEERXSA-N
IUPAC Name	[(19S)-10,19-diethyl-19-hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2,4(9),5,7,10,15(20)-heptaen-7-yl] 4-piperidin-1-ylpiperidine-1-carboxylate

The activity data of This Drug

Standard Type	Value	Disease Model	Cell line	Cell line ID	Ref.
Half Maximal Growth Inhibition (GI50)	>1000 nM	Invasive breast carcinoma	MCF-7 cell	CVCL_0031	[1]
Half Maximal Growth Inhibition (GI50)	7.1 uM	Colon carcinoma	HCT 116 cell	CVCL_0291	[2]
Half Maximal Growth Inhibition (GI50)	9.17 uM	Breast adenocarcinoma	MDA-MB-231 cell	CVCL_0062	[3]
Half Maximal Growth Inhibition (GI50)	>10 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[3]
Half Maximal Infective Dose (ID50)	>500 nM	High grade ovarian serous adenocarcinoma	NCI-ADR-RES cell	CVCL_1452	[4]
Half Maximal Inhibitory Concentration (IC50)	4 nM	Prostate carcinoma	PC-3 cell	CVCL_0035	[5]
Half Maximal Inhibitory Concentration (IC50)	4 nM	Amelanotic melanoma	A-375 cell	CVCL_0132	[5]
Half Maximal Inhibitory Concentration (IC50)	6.9 nM	Colon adenocarcinoma	T84 cell	CVCL_0555	[6]
Half Maximal Inhibitory Concentration (IC50)	9 nM	Prostate carcinoma	LNCaP cell	CVCL_0395	[5]
Half Maximal Inhibitory Concentration (IC50)	15 nM	Lung large cell carcinoma	NCI-H460 cell	CVCL_0459	[5]
Half Maximal Inhibitory Concentration (IC50)	27 nM	Lung large cell carcinoma	NCI-H460 cell	CVCL_0459	[5]
Half Maximal Inhibitory Concentration (IC50)	32 nM	Acute myeloid leukemia	HL-60 cell	CVCL_0002	[7]
Half Maximal Inhibitory Concentration (IC50)	200 nM	Prostate carcinoma	DU145 cell	CVCL_0105	[5]
Half Maximal Inhibitory Concentration (IC50)	220 nM	Colon cancer	HT29 cell	CVCL_A8EZ	[5]
Half Maximal Inhibitory Concentration (IC50)	250 nM	Lung small cell carcinoma	H69AR cell	CVCL_3513	[5]
Half Maximal Inhibitory Concentration (IC50)	570 nM	T acute lymphoblastic leukemia	RPMI-8402 cell	CVCL_1667	[8]
Half Maximal Inhibitory Concentration (IC50)	800 nM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[9]
Half Maximal Inhibitory Concentration (IC50)	900 nM	Invasive breast carcinoma	MCF-7 cell	CVCL_0031	[10]
Half Maximal Inhibitory Concentration (IC50)	1.2 uM	Lymphoblastic leukemia	L1210 cell	CVCL_0382	[11]
Half Maximal Inhibitory Concentration (IC50)	1.5 uM	Pancreatic ductal adenocarcinoma	Capan-1 cell	CVCL_0237	[12]
Half Maximal Inhibitory Concentration (IC50)	1.557 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[13]
Half Maximal Inhibitory Concentration (IC50)	1.9 uM	Colon cancer	HT29 cell	CVCL_A8EZ	[10]
Half Maximal Inhibitory Concentration (IC50)	3.55 uM	Colon cancer	HT29 cell	CVCL_A8EZ	[14]
Half Maximal Inhibitory Concentration (IC50)	5.15 uM	Lung large cell carcinoma	NCI-H460 cell	CVCL_0459	[15]
Half Maximal Inhibitory Concentration (IC50)	6.3 uM	Amelanotic melanoma	MDA-MB-435 cell	CVCL_0417	[16]
Half Maximal Inhibitory Concentration (IC50)	6.4 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[17]
Half Maximal Inhibitory Concentration (IC50)	7.99 uM	Human papillomavirus-related endocervical adenocarcinoma	KB cell	CVCL_0372	[18]
Half Maximal Inhibitory Concentration (IC50)	8.3 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[19]
Half Maximal Inhibitory Concentration (IC50)	8.31 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[18]
Half Maximal Inhibitory Concentration (IC50)	8.8 uM	Colon adenocarcinoma	LoVo cell	CVCL_0399	[17]
Half Maximal Inhibitory Concentration (IC50)	9.5 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[20]
Half Maximal Inhibitory Concentration (IC50)	9.7 uM	Colon carcinoma	HCT 116 cell	CVCL_0291	[21]
Half Maximal Inhibitory Concentration (IC50)	>10 uM	Mantle cell lymphoma	JeKo-1 cell	CVCL_1865	[12]
Half Maximal Inhibitory Concentration (IC50)	>10 uM	Diffuse large B-cell lymphoma	OCI-Ly3 cell	CVCL_8800	[12]
Half Maximal Inhibitory Concentration (IC50)	>10 uM	Burkitt lymphoma	DG-75 cell	CVCL_0244	[12]
Half Maximal Inhibitory Concentration (IC50)	11.32 uM	Invasive breast carcinoma	MCF-7 cell	CVCL_0031	[18]
Half Maximal Inhibitory Concentration (IC50)	12.3 uM	Colon adenocarcinoma	SW480 cell	CVCL_0546	[22]
Half Maximal Inhibitory Concentration (IC50)	16.53 uM	Lung adenocarcinoma	A-549 cell	CVCL_0023	[23]
Half Maximal Inhibitory Concentration (IC50)	17.403 uM	Invasive breast carcinoma	MCF-7 cell	CVCL_0031	[24]
Half Maximal Inhibitory Concentration (IC50)	18 uM	Breast carcinoma	ZR-75-30 cell	CVCL_1661	[25]
Half Maximal Inhibitory Concentration (IC50)	18.81 uM	Lung squamous cell carcinoma	NCI-H2170 cell	CVCL_1535	[15]
Half Maximal Inhibitory Concentration (IC50)	>100 uM	Hepatoblastoma	Hep-G2 cell	CVCL_0027	[26]
Half Maximal Inhibitory Concentration (IC50)	>100 uM	Colon carcinoma	HCT 116 cell	CVCL_0291	[26]

Each Peptide-drug Conjugate Related to This Drug

Full Information of The Activity Data of The PDC(s) Related to This Drug

BGC-0222 [Phase 1]

PDC Info

Discovered Using Cell Line-derived Xenograft Model

Click To Hide/Show 19 Activity Data Related to This Level

Experiment 1 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	9.21%
Administration Time	32 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 2 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	9.87%
Administration Time	29 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 3 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	16.90%
Administration Time	25 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 4 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	27.60%
Administration Time	22 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 5 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	57.00%
Administration Time	18 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 6 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	88.80%
Administration Time	15 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 7 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor increment rates values	100%
Administration Time	12 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 8 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Tumor Growth Inhibition value (TGI)	90%
Administration Time	32 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 9 Reporting the Activity Data of This PDC				[27]
Indication	Glioblastoma
Efficacy Data	Tumor Growth Inhibition value (TGI)	94%
Administration Time	40 days
Administration Dosage	60 mg/kg, QW3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse U-87MG cells xenograft model.
In Vitro Model	Glioblastoma	U-87MG cell	CVCL_0022
Experiment 10 Reporting the Activity Data of This PDC				[27]
Indication	Small cell lung cancer
Efficacy Data	Tumor Growth Inhibition value (TGI)	95%
Administration Time	30 days
Administration Dosage	20 mg/kg, QW3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse NCI-H446 cells xenograft model.
In Vitro Model	Lung small cell carcinoma	NCI-H446 cell	CVCL_1562
Experiment 11 Reporting the Activity Data of This PDC				[27]
Indication	Pancreatic ductal adenocarcinoma
Efficacy Data	Tumor Growth Inhibition value (TGI)	98%
Administration Time	31 days
Administration Dosage	20 mg/kg, QW3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse MIA PaCa-2 cells xenograft model.
In Vitro Model	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	CVCL_0428
Experiment 12 Reporting the Activity Data of This PDC				[27]
Indication	Breast cancer
Efficacy Data	Tumor Growth Inhibition value (TGI)	99%
Administration Time	36 days
Administration Dosage	20 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse MDA-MB-231 cells xenograft model.
In Vitro Model	Breast adenocarcinoma	MDA-MB-231 cell	CVCL_0062
Experiment 13 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	0.72
Administration Time	29 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 14 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	0.82
Administration Time	32 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 15 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	0.88
Administration Time	25 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 16 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	1
Administration Time	12 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 17 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	1.15
Administration Time	22 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 18 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	1.47
Administration Time	15 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 19 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Relative tumor volume (RTV)	1.56
Administration Time	18 days
Administration Dosage	40 mg/kg, Q4D3
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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. Click to Show/Hide
In Vivo Model	Female Balb/c nude mouse HT-29 cells xenograft model.
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ

Revealed Based on the Cell Line Data

Click To Hide/Show 3 Activity Data Related to This Level

Experiment 1 Reporting the Activity Data of This PDC				[27]
Indication	Breast cancer
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	0.68 ± 0.04 μM
Evaluation Method	Graph Pad Prism 5.0
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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 μM) and NKTR-102 (IC50 = 2.02 0.10 μM), with IC50 value of 1.83 0.09 μM. In addition, compound BGC0222 showed better antiproliferative activity than irinotecan (IC50 = 16.2 0.22 μM) and NKTR-102 (IC50 = 4.68 0.15 μM) against MIA PaCa-2 cells line, with IC50 value of 3.95 0.16 μM, while compound BGC0222 also exhibited stronger antiproliferative activity than irinotecan (IC50 = 2.69 0.12 μM) and NKTR-102 (IC50 = 0.71 0.05 μM) in MCF-7 cells line assay, with IC50 value of 0.68 0.04 μM, 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. Click to Show/Hide
In Vitro Model	Invasive breast carcinoma	MCF-7 cell	CVCL_0031
Experiment 2 Reporting the Activity Data of This PDC				[27]
Indication	Colon adenocarcinoma
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	1.83 ± 0.09 μM
Evaluation Method	Graph Pad Prism 5.0
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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 μM) and NKTR-102 (IC50 = 2.02 0.10 μM), with IC50 value of 1.83 0.09 μM. In addition, compound BGC0222 showed better antiproliferative activity than irinotecan (IC50 = 16.2 0.22 μM) and NKTR-102 (IC50 = 4.68 0.15 μM) against MIA PaCa-2 cells line, with IC50 value of 3.95 0.16 μM, while compound BGC0222 also exhibited stronger antiproliferative activity than irinotecan (IC50 = 2.69 0.12 μM) and NKTR-102 (IC50 = 0.71 0.05 μM) in MCF-7 cells line assay, with IC50 value of 0.68 0.04 μM, 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. Click to Show/Hide
In Vitro Model	Colon cancer	HT29 cell	CVCL_A8EZ
Experiment 3 Reporting the Activity Data of This PDC				[27]
Indication	Pancreatic ductal adenocarcinoma
Efficacy Data	Half Maximal Inhibitory Concentration (IC50)	3.95 ± 0.16 μM
Evaluation Method	Graph Pad Prism 5.0
MOA of PDC	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 αv3), 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 αv3) 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 αv3 and αv5 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. Click to Show/Hide
Description	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 μM) and NKTR-102 (IC50 = 2.02 0.10 μM), with IC50 value of 1.83 0.09 μM. In addition, compound BGC0222 showed better antiproliferative activity than irinotecan (IC50 = 16.2 0.22 μM) and NKTR-102 (IC50 = 4.68 0.15 μM) against MIA PaCa-2 cells line, with IC50 value of 3.95 0.16 μM, while compound BGC0222 also exhibited stronger antiproliferative activity than irinotecan (IC50 = 2.69 0.12 μM) and NKTR-102 (IC50 = 0.71 0.05 μM) in MCF-7 cells line assay, with IC50 value of 0.68 0.04 μM, 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. Click to Show/Hide
In Vitro Model	Pancreatic ductal adenocarcinoma	MIA PaCa-2 cell	CVCL_0428

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Prof. Feng Zhu

Prof. Qingzhong Jia

Prof. Leo, Lianyi Han