The pH-sensitive chondroitin sulphate-based nanoparticles for co-delivery of doxorubicin and berberine enhance the treatment of breast cancer

In the tumor microenvironment (TME), cancer associated fibroblasts (CAFs) facilitate drug resistance and tumor metastasis. Therefore, more and more attention has been focused on the regulation of TME by preventing the cross-talk between tumor cells and CAFs in the treatment of breast cancer. In this study, we have combined the benefits of deep drug penetration, pH sensitivity, and tumor-targeting delivery to prepare chondroitin sulphate (CS)-based nanomicelles (BBR/CS-DOX) for the co-delivery of doxorubicin (DOX) and berberine (BBR). A unique MCF-7 + MRC-5 co-cultured cell model and 4 T1 + NIH3T3 co-implanted mice model, were established to simulate the TME of breast cancer (BC). As expected, BBR/CS-DOX could accumulate in tumor egion, be taken up by both tumor cells and CAFs, and improve drug absorption and retention. Compared with free drugs, BBR/CS-DOX demonstrated stonger pro-apoptotic and anti-metastatic effect in vitro and in vivo, respectively the histological studies showed that BBR/CS-DOX efficiently prevented the activation of fibroblasts, inhibited extracellular matrix (ECM) deposition, and decreased tumor angiogenesis, showing superior anti-tumor efficacy. In summary, BBR/CS-DOX has the potential to significantly enhance the therapeutic effect of breast cancer through inhibiting the "CAFs-tumor cells" crosstalk, and has promising clinical application prospects.