Targeted delivery of therapeutic agent meets with hurdle of finding target ligand or receptor those are expressed tumor cells in homogenous patterns but not on normal cells. Apoptosis is an event that is programmed in all cells exposed to specific stimuli and this phenotypic event does not vary in patient to patient. In attempt to overcome limitations of conventional targeted therapy, radiation-induced apoptosis-targeted chemotherapy (RIATC) was suggested in our previous study. Caspase-3 cleavable docetaxel prodrug is treated following local administration of low dose radiation in tumor site which induces apoptosis. After initial activation of the prodrug, in-situ amplification of prodrug from expressed caspase-3 boost further activation of the prodrug.
We designed EMC-KGDEVD-PABC-DCX containing albumin binding maleimide moiety, and docetaxel linked to a caspase-3 cleavable peptide moiety (DEVD). To upregulate caspase-3 expression in the tumor site, we used radiation to induce apoptosis in target tumor site. EMC-KGDEVD-PABC-DCX combined with multiple dose radiation was administered in breast tumor bearing balb/c nu mice. Toxicities profile of EMC-KGDEVD-PABC-DCX were evaluated.
EMC-KGDEVD-PABC-DCX was activated in the tumor site and free docetaxel was relased out to exert cytotoxic effects on neighboring tumor cells, which repetitively induced the expression of caspase-3. We have achieved complete response of 60% and 80% for 1 mg/kg and 3 mg/kg of EMC-KGDEVD-DCX combined with radiotherapy. No severe toxicities were observed in our treatment doses.
Upon activation of the prodrug, free docetaxel can be released out and exert its cytotoxic effect to bystander cancer cells by stabilising microtubule assembly. Therefore, with our novel therapy using peptide-docetaxel conjugate, outstanding tumor killing effect can be exhibited selectively in tumor site with reducing side effects to normal tissues.
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University
All authors have declared no conflicts of interest.