Dextran-based redox-responsive doxorubicin prodrug micelles for overcoming multidrug resistance

Abstract

Multidrug resistance (MDR) is one of the critical reasons for the failure of cancer chemotherapy. To overcome MDR, we have developed redox-responsive doxorubicin prodrug (DEX-PEI(-SS-DOX)) micelles based on dextran-poly(ethylene imine) copolymers (DEX-PEI). The DEX-PEI(-SS-DOX) conjugates were conveniently prepared by grafting PEI to dextran, and then the anticancer drug doxorubicin (DOX) was conjugated to DEX-PEI through redox-responsive cleavable disulfide linkers. The amphiphilic DOX prodrug self-assembled into micelles in aqueous solution and the micelles showed an average size of 100–140 nm with a uniform spherical morphology. In vitro drug release studies showed that the prodrug micelles accomplished rapid drug release under reducing conditions. Confocal images revealed that the micelles enhance the cellular accumulation of DOX and achieve endosomal escape in human breast carcinoma multidrug resistant (MCF-7/ADR) cells. The therapeutic efficacy of the self-assembled DOX prodrug micelles against MCF-7/ADR cells in vitro was evaluated through the MTT assay. The results showed that the therapeutic efficacy of DOX prodrug micelles against MCF-7/ADR cells was remarkably enhanced compared with free DOX. These results indicate that the redox-responsive DOX prodrug micelles could be a promising delivery system for overcoming MDR.