General Information of This Peptide
Peptide ID
PEP00066
Peptide Name
KKKRLNVGGTYFLTTRQ
Structure
Sequence
KKKRLNVGGTYFLTTRO
Peptide Type
Linear
Receptor Name
Glypican-3 (GPC3)
 Receptor Info 
PDC Transmembrane Types Cell-penetrating peptides (CPPs)
Formula
C90H152N28O24
Isosmiles
[H]NCCCC[C@H](N[H])C(=O)N[C@@H](CCCCN[H])C(=O)N[C@@H](CCCCN[H])C(=O)N[C@@H](CCC/N=C(/N)N[H])C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)N[H])C(=O)N[C@H](C(=O)NCC(=O)NCC(=O)N[C@]([H])(C(=O)N[C@@H](Cc1ccc(O[H])cc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@]([H])(C(=O)N[C@]([H])(C(=O)N[C@@H](CCC/N=C(/N)N[H])C(=O)N[C@@H](CCC(=O)N[H])C(=O)O)[C@@H](C)O[H])[C@@H](C)O[H])[C@@H](C)O[H])C(C)C
InChI
InChI=1S/C90H152N28O24/c1-46(2)39-61(110-78(131)58(26-19-37-101-89(97)98)107-76(129)57(25-15-18-36-93)106-75(128)56(24-14-17-35-92)105-74(127)55(94)23-13-16-34-91)79(132)113-65(43-67(96)124)83(136)116-70(48(5)6)84(137)104-44-68(125)103-45-69(126)115-71(49(7)119)85(138)114-64(42-53-28-30-54(122)31-29-53)81(134)112-63(41-52-21-11-10-12-22-52)80(133)111-62(40-47(3)4)82(135)117-73(51(9)121)87(140)118-72(50(8)120)86(139)108-59(27-20-38-102-90(99)100)77(130)109-60(88(141)142)32-33-66(95)123/h10-12,21-22,28-31,46-51,55-65,70-73,119-122H,13-20,23-27,32-45,91-94H2,1-9H3,(H2,95,123)(H2,96,124)(H,103,125)(H,104,137)(H,105,127)(H,106,128)(H,107,129)(H,108,139)(H,109,130)(H,110,131)(H,111,133)(H,112,134)(H,113,132)(H,114,138)(H,115,126)(H,116,136)(H,117,135)(H,118,140)(H,141,142)(H4,97,98,101)(H4,99,100,102)/t49-,50-,51-,55+,56+,57+,58+,59+,60+,61+,62+,63+,64+,65+,70+,71+,72+,73+/m1/s1
InChIKey
YIIYNOVFQASQRF-CIRWCEOVSA-N
Pharmaceutical Properties
Molecule Weight
2010.378
Polar area
902.88
Complexity
2009.153428
xlogp Value
-9.8654
Heavy Count
142
Rot Bonds
78
Hbond acc
29
Hbond Donor
31
The Activity Data of This Peptide
Peptide Activity Information 1 [1]
Fluorescence polarization 0.08
Binding Affinity Assay
A fluorescence polarization test was performed to measure the binding affinity between PS conjugates and GPC3.
Experimental Condition GPC3 protein in vitro
Each Peptide-drug Conjugate Related to This Peptide
Full Information of The Activity Data of The PDC(s) Related to This Peptide
Glypican-3-targeting peptide-chlorin e6 conjugates 8d [Investigative]
Revealed Based on the Cell Line Data
Click To Hide/Show 10 Activity Data Related to This Level
Experiment 1 Reporting the Activity Data of This PDC [1]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.33 ± 0.01 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

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Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

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In Vitro Model Hepatoblastoma L-O2 cell line CVCL_0027
Experiment 2 Reporting the Activity Data of This PDC [1]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.34 ± 0.01 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

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In Vitro Model Adult hepatocellular carcinoma GPC3-positive Huh-7 cell CVCL_0336
Experiment 3 Reporting the Activity Data of This PDC [1]
Indication Solid tumor
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.38 ± 0.03 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Normal Human umbilical vein endothelial cell Homo sapiens
Experiment 4 Reporting the Activity Data of This PDC [1]
Indication Cervical cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.57 ± 0.05 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Human papillomavirus-related cervical adenocarcinoma GPC3-negative HeLa cell CVCL_0030
Experiment 5 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50)
0.79 ± 0.01 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Invasive breast carcinoma GPC3 negative MCF7 cell CVCL_0031
Experiment 6 Reporting the Activity Data of This PDC [1]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 200 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Hepatoblastoma L-O2 cell line CVCL_0027
Experiment 7 Reporting the Activity Data of This PDC [1]
Indication Liver cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 200 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Adult hepatocellular carcinoma GPC3-positive Huh-7 cell CVCL_0336
Experiment 8 Reporting the Activity Data of This PDC [1]
Indication Breast cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 200 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Invasive breast carcinoma GPC3 negative MCF7 cell CVCL_0031
Experiment 9 Reporting the Activity Data of This PDC [1]
Indication Cervical cancer
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 200 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Human papillomavirus-related cervical adenocarcinoma GPC3-negative HeLa cell CVCL_0030
Experiment 10 Reporting the Activity Data of This PDC [1]
Indication Solid tumor
Efficacy Data Half Maximal Inhibitory Concentration (IC50) > 200 µM
Administration Time 24 h
Evaluation Method Annexin V/PI staining assay
MOA of PDC
Hepatocellular carcinoma (HCC) is a highly aggressive and lethal malignancy with poor prognosis, necessitating the urgent development of effective treatments. Targeted photodynamic therapy (PDT) offers a promising way to selectively eradicate tumor cells without affecting normal cells. Inspired by promising features of peptide-drug conjugates (PDCs) in targeted cancer therapy, herein a novel glypican-3 (GPC3)-targeting PDC-PDT strategy was developed for the precise PDT treatment of HCC. The GPC3-targeting photosensitizer conjugates were developed by attaching GPC3-targeting peptides to chlorin e6. Conjugate 8b demonstrated the ability to penetrate HCC cells via GPC3-mediated entry process, exhibiting remarkable tumor-targeting capacity, superior antitumor efficacy, and minimal toxicity towards normal cells. Notably, conjugate 8b achieved complete tumor elimination upon light illumination in a HepG2 xenograft model without harm to normal tissues. Overall, this innovative GPC3-targeting conjugation strategy demonstrates considerable promise for clinical applications for the treatment of HCC.

   Click to Show/Hide
Description
Subsequently, the antiproliferative activities of the PS conjugates, including dark toxicity and phototoxicity (660 nM, light dose: 10 J/cm2), were evaluated. Dark toxicity refers to the toxicity of PS conjugates against cancer cells in the absence of light and can be regarded as a crucial measure of the safety profile, while phototoxicity is the most direct indicator of the PDT efficacy of PS. The results showed that the dark toxicity of all the compounds against the five cell lines was comparatively low, demonstrating that the PS conjugates exhibited a high safety index in the absence of light. Compound 8b exhibited the optimum tumor cell selectivity in terms of phototoxicity, with the IC50 values of 0.82 uM against HepG2 cells and 2.4 uM against Huh-7 cells, respectively, whereas its toxicity against GPC3-negative cell lines was >10 uM. Although compounds 8a and 8c-d exhibited excellent phototoxicity against HepG2 and Huh-7 cells, (IC50 range: 0.2-2.0 uM), these compounds lacked selectivity between GPC3-overexpressed and GPC3-negative cells because they also showed considerable phototoxicity against the cell lines with minimal GPC3 expression. Notably, compound 1 showed low phototoxicity and selectivity against all the tested cell lines (IC50 > 10 uM).

   Click to Show/Hide
In Vitro Model Normal Human umbilical vein endothelial cell Homo sapiens
References
Ref 1 Smart glypican-3-targeting peptide-chlorin e6 conjugates for targeted photodynamic therapy of hepatocellular carcinoma. Eur J Med Chem. 2024 Jan 15;264:116047. doi: 10.1016/j.ejmech.2023.116047. Epub 2023 Dec 16.