A novel FAPα-based Z-Gly-Pro epirubicin prodrug for improving tumor-targeting chemotherapy

Fibroblast activation protein-α (FAPα) is a serine protease of the post-prolyl peptidase family that is specifically expressed in the majority of human epithelial tumors, but not in normal tissues. In this study, we demonstrated the anti-tumor activity of a novel targeting drug formed by conjugating...

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Bibliographic Details
Published in:European journal of pharmacology 2017-11, Vol.815, p.166-172
Main Authors: Wang, Jun, Li, Qiuwen, Li, Xiaojuan, Yuan, Weiqi, Huang, Sichao, Cai, Shaohui, Xu, Jun
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - adverse effects
Antineoplastic Agents - chemistry
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Cardiotoxicity
Cell Line, Tumor
Dipeptide (Z-Gly-Pro)
EPI
Epirubicin - adverse effects
Epirubicin - chemistry
Epirubicin - metabolism
Epirubicin - pharmacology
Female
Fibroblast activation protein-α (FAPα)
Gelatinases - metabolism
Heart - drug effects
Humans
Membrane Proteins - metabolism
Mice
Prodrug
Prodrugs - metabolism
Proteolysis
Serine Endopeptidases - metabolism
Targeting
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Summary:Fibroblast activation protein-α (FAPα) is a serine protease of the post-prolyl peptidase family that is specifically expressed in the majority of human epithelial tumors, but not in normal tissues. In this study, we demonstrated the anti-tumor activity of a novel targeting drug formed by conjugating epirubicin (EPI) with an FAPα-specific dipeptide (Z-Gly-Pro) and named it Z-GP-EPI. Consistent with this tumor-targeting delivery strategy, the results illustrated that Z-GP-EPI could release EPI efficiently after incubating with FAPα and could exhibit similar antitumor effects as EPI in vitro in FAPα over-expressed tumor cells (4T1/FAPα+). Furthermore, the evaluation of antitumor activity of Z-GP-EPI in vivo was implemented in a 4T1/FAPα+ tumor-bearing mice xenograft model. Our results illustrated that Z-GP-EPI had similar antitumor effects in 4T1/FAPα+ tumor-bearing mice and showed no visible cardiotoxicity side effects compared with free EPI. Thus, our study indicated that this FAPα-activated prodrug targeting strategy may provide a new mechanism for the targeted delivery of antitumor agents and improve their safety levels.
ISSN:0014-2999
1879-0712
DOI:10.1016/j.ejphar.2017.09.016