Mixtures of Doxorubicin-Loaded Micelles and Berberine and Mifepristone Co-Loaded Liposomes Inhibit Breast Cancer Metastasis Based on Regulation of Tumor Microenvironments

Abstract

Tumor microenvironment (TME) plays an important role in breast cancer metastasis. More and more attention has been attracted on the combination of TME-modulating and chemotherapeutic approaches. In this study, mixed nanosized vehicles composed of doxorubicin (Dox)-loaded micelles (D-HMs) and Berberine&Mifepristone (Ru486) co-loaded liposomes (B&R-HLs) were prepared to inhibit breast cancer metastasis. The in vitro "MCF-7/MRC-5" dual-cell model and the in vivo orthotopic 4T1-cellbearing mice model were built to detect the anti-cancer effect of D-HMs/B&R-HLs. The characteristic results showed that D-HMs with a compact size of approximately 30 nm could deeply infiltrate the tumor tissue, while B&R-HLs were 120 nm in particle size and released amounts of drugs in an acidic environment. Compared with other groups, the mixed vehicles showed stronger cytotoxiciy and an anti-migration effect. The in vivo anti-tumor studies showed D-HMs/B&R-HLs could effectively inhibit tumor growth and metastasis, block the activation of cancer-associated fibroblasts (CAFs), decrease extracellular matrix (ECM) deposition and tumor angiogenesis, and increase the proportion of cytotoxic T cells. These results showed that the mixed vehicles could effectively modulate the TME, leading to a synergetic anti-metastasis effect. In brief, D-HMs/B&R-HLs are a potential drug delivery system, which could obviously inhibit breast cancer metastasis.