A co-delivery system based on a reduction-sensitive polymeric prodrug capable of loading hydrophilic and hydrophobic drugs for combination chemotherapy

Abstract

Herein, we report a co-delivery system based on poly(ethylene glycol)-b-poly(5-methyl-5-propargyl-1,3-dioxan-2-one) (PEG-b-PMPMC) for cancer treatment. A reduction-sensitive PTX prodrug (azido-SS-PTX) was grafted onto PEG-b-PMPMC by azide–alkyne click reaction to give a reduction-sensitive polymeric prodrug, PEG-b-PMPMC-g-PTX, with a well-defined structure and narrow molecular weight distribution. Interestingly, the polymeric prodrug could self-assemble into micelles or polymersomes in aqueous solution based on the particular graft ratio of PTX on the polycarbonate backbone, which endowed it with a possibility to encapsulate a hydrophobic drug (e.g., doxorubicin, DOX) or a hydrophilic drug (e.g., doxorubicin hydrochloride, DOX·HCl) for combination chemotherapy. To promote the stability and on-demand drug release, the self-assemblies of PEG-b-PMPMC-g-PTX were further crosslinked by a reduction-sensitive crosslinker to prepare reversibly crosslinked nanoparticles. The drug release from the carriers was suppressed under normal physiological conditions, whereas markedly accelerated under 10 mM dithiothreitol (DTT) conditions. The dual drug-loaded nanoparticles exhibited significant growth-inhibition for HeLa cells and drug-resistant MCF-7/ADR cells compared with the single drug-loaded nanoparticles, especially for drug resistant tumor cells. More importantly, DOX·HCl-loaded polymersomes of the polymeric prodrug exhibited a synergistic effect of cell-growth inhibition on HeLa cells. These results indicated that the co-delivery system based on reduction-sensitive polymeric prodrugs would be a promising technology in cancer therapy to overcome multidrug resistance (MDR).