The novel strategy for concurrent chemoradiotherapy by conjugating the apoptotic cell-binding moiety to caspase-3 activated doxorubicin prodrug

• Published in: Journal of controlled release 2019-02, Vol.296, p.241-249
• Main Authors: Cho, Young Seok, Chung, Seung Woo, Kim, Ha Rin, Won, Tae Hyung, Choi, Jeong Uk, Kim, In-San, Kim, Sang Yoon, Byun, Youngro
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Apoptosis - drug effects; Caspase 3 - metabolism; Cell Line, Tumor; Chemoradiotherapy; Doxorubicin - administration & dosage; Doxorubicin - pharmacokinetics; Female; Humans; Liver - drug effects; Liver - pathology; Mice, Inbred BALB C; Mice, Nude; Myocardium - pathology; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Oligopeptides - administration & dosage; Oligopeptides - pharmacokinetics; Prodrugs - administration & dosage; Prodrugs - pharmacokinetics; Tumor Burden - drug effects
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2019.01.020

The selective targeting of cytotoxic agents to a tumor has shown limited success by difficulties in identifying the appropriate target molecules, and more importantly, by the phenotypically dynamic nature of the tumor cells and intratumoral heterogeneity. In an attempt to overcome these issues and efficiently deliver cytotoxic drugs to the tumor, we previously reported a strategy termed radiation-induced apoptosis-targeted chemotherapy (RIATC), which utilizes the radiotherapy for intentionally triggering the caspase-3 and in situ amplification of tumor apoptosis by caspase-3 activated prodrug. Herein, we propose an advanced form of RIATC prodrug, AP1-DEVD-S-DOX, that could more actively target to the ligands of radiation-induced tumor cells, which could accumulate more prodrugs, thereby allowing more effective in situ activation and amplification of tumor apoptosis, comparing to RIATC. Indeed, AP1-DEVD-S-DOX was able to exert improved doxorubicin (DOX) delivery to the tumor and anticancer effect than the RIATC prodrug that lacks apoptotic cell-binding property but having a similar degree of off-target distribution in the other organs. Accordingly, AP1-DEVD-S-DOX could be an efficient prodrug for concurrent chemoradiotherapy by selectively delivering doxorubicin to the tumor with less systemic cytotoxicity. [Display omitted]