Environmental responsive dual-drug synergistic and dual-targeted polymer micelles based on chondroitin sulfate for treatment of breast cancer

Targeted drug delivery strategy can accurately deliver multiple drugs to tumor cells by biocompatible materials, enhance the therapeutic effect and weaken adverse side effects. Chondroitin sulfate (CS) is a biodegradable material which has dual-targeting ability to CD44 receptors and Golgi apparatus. Flurbiprofen is a COX-2 inhibitor that can be used as an anticancer adjuvant in combination with docetaxel to enhance the antitumor effect. Herein, docetaxel and flurbiprofen were coupled to CS via disulfide bond and ester bond respectively to prepare polymer conjugates chondroitin sulfate-docetaxel (C-ss-D) and chondroitin sulfate-flurbiprofen (C-F). Then the reduction-sensitive micelles C-ss-D and the pH-sensitive micelles C-F were constructed by self-assembly respectively, and the dual-drug micelles C-F/C-ss-D were further prepared. C-F/C-ss-D displayed uniform spherical shape, negative surface charge, and achieved controlled drug release in slightly acidic and reductive tumor microenvironment. C-F/C-ss-D exhibited remarkable targeting ability towards tumor cells and Golgi apparatus, demonstrated potent cytotoxic effect on MCF-7 cells, and induced apoptosis by regulating the expression of COX-2 and apoptosis-related proteins. C-F/C-ss-D effectively inhibited tumor growth in MCF-7 xenograft mice with low toxicity to blood and major organs. Therefore, the environmental responsive dual-drug synergistic and dual-targeted micelles based on CS have great potential for the treatment of breast cancer.