Mixed polymeric micelles for combination cancer chemotherapy through the concurrent delivery of multiple chemotherapeutic agents

Abstract

As a novel drug nanocarrier for combination delivery of multiple anticancer agents, mixed polymeric micelles were developed and characterized in this study. A DNA-damaging anthracycline agent doxorubicin (DOX) and a phosphatidylinositol-3 kinase inhibitor wortmannin (WOR) were conjugated alone or combination onto poly(ethylene glycol)-poly(aspartate hydrazide) block copolymers through a hydrazone bond. Polymer–drug conjugates assembled into a unimodal micelle structure with a < 100 nm particle size, in which the drug mixing ratios between DOX/WOR were precisely controlled. Cytotoxicity assay against a human breast cancer MCF-7 cell line showed that drug nanocarrier based on mixed polymeric micelles can reduce DOX required for cytotoxicity while maintaining the biological activity of the independent polymeric micelles. It is postulated that WOR enhances the efficacy of DOX through an efficient combination delivery accompanied by synergistic drug action. These findings, therefore, bring an effective drug delivery methodology that might reduce the effective dose as well as toxicity in vivo compared to the conventional drug formulations.