Microenvironmental-Regulated Chondroitin Sulfate Nanomicelles for Inhibition of Breast Cancer Drug Resistance and Metastasis

Abstract Tumor microenvironment is closely involved in breast cancer progression and metastatic spread. Therefore, it is essential to develop a combination therapy to suppress tumor progression by regulating TME. Herein, Ru486-loaded doxorubicin (DOX)–chondroitin sulfate (chondroitin sulfate) nanomicelles (R/D-CS) were prepared for combined delivery. A “MCF-7 + MRC-5” dual-cell model and “4T1 + NIH-3T3” cell-bearing mouse model were established to recapitulate TME in vitro and in vivo, respectively. Interestingly, R/D-CS nanomicelles internalized cancer-associated fibroblasts and tumor cells and reduced tumor proliferation and migration markedly by downregulating expression of P-gp, vimentin, and CXCR4. Moreover, the in vivo antitumor studies were performed on a tumor-bearing mouse model, R/D-CS nanomicelles showed stronger antiproliferative and antimetastatic effects. Overall, the combination therapy based on R/D-CS nanomicelles was potent for breast cancer treatment.