Decitabine/paclitaxel co-delivery systems modified with anti-PD-L1 antibodies mediate chemoimmunotherapy for Triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is one of the major clinical problems to be solved urgently, because of its high malignancy, poor targeted therapy effect and easy occurrence of drug resistance and metastasis. Here, methyltransferase DNMT1 was identified as a key factor mediating PTX resistance for TNBC. Decitabine (DEC), an inhibitor of DNMT1, can inhibit the proliferation and metastasis of TNBC cells and reverse PTX resistance. In this study, we reported a new delivery system (DEC/PTX NPs@αPD-L1) co-loaded with DEC and PTX modified by anti-PD-L1 monoclonal antibody (αPD-L1), which can overcome drug resistance and metastasis through multi-mode synergistic effect. αPD-L1 increases the enrichment of nanoparticles in tumor tissue through active targeting effect, and blocks PD-L1 on the surface of TNBC cells, thereby activating anti-tumor immune while enhancing internalization of nanoparticles by tumor cells. Inside tumor cells, DEC inhibits EMT process and cancer stem cells to overcome PTX resistance and metastasis. PTX can not only exerts direct tumor killing effect, but also inhibit Treg cells from remodeling immune microenvironment, and induces efficient immunogenic death in cooperation with DEC. This delivery system, realizing tumor-specific synchronized chemoimmunotherapy, represents a promising therapeutic platform for TNBC.