Dual-acidity-labile polysaccharide-di-drugs conjugate for targeted cancer chemotherapy

摘要

Polymer-drug conjugates synthesized by binding therapeutic agents to functional polymers have long been a mainstay of prodrugs, while the slow drug release, insufficient efficacy of a single drug, and low selectivity hamper the clinical translation. By rational prodrug design, a targeted dual-acidity-labile polysaccharide-di-drugs conjugate was synthesized by one-pot simultaneous Schiff base and boronic esterification reactions between oxidized dextran (Dex-CHO) and cyclo-(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)), doxorubicin (DOX), and bortezomib (BTZ). The polysaccharide-di-drugs conjugate (Dex-g-(DOX+BTZ)/cRGD) self-assembled into micelle with a diameter at around 80 nm and released the drugs simultaneously triggered by the acidic conditions. Dex-g-(DOX+BTZ)/cRGD specifically recognized and entered the cancer cells through the RGD-alpha(v)beta(3) integrin interplay, selectively released DOX and BTZ in the acidic intracellular microenvironment, and efficiently inhibited the cell proliferation in vitro. More importantly, Dex-DOX/BTZ/cRGD showed higher intratumoral accumulation and better antitumor efficacy in vivo compared with free drugs and non-targeted control prodrug Dex-g-(DOX+BTZ). The findings indicated that this study provided a facile strategy to develop smart polymer-multi-drugs conjugates for targeted cancer chemotherapy. (C) 2020 Elsevier Masson SAS. All rights reserved.