Co-delivery Of Polymer Micelles To Reshape The Tumor Microenvironment Combined With APD-1 To Enhance The Chemotherapy-immunotherapy Effect Of Triple-negative Breast Cancer

Due to the heterogeneous tumor microenvironment of triple-negative breast cancer(TNBC),the existing treatment methods are difficult to produce long-term and effective treatment effects.In recent years,immunotherapy with PD-1 inhibitors has achieved significant results in clinical applications,but its disadvantages are the low tumor response rate and the inability to achieve long-term effective treatment.Studies have shown that a small number of chemotherapeutic drugs,such as paclitaxel(Paclitaxel,PTX),can promote the maturation of dendritic cells(DC)and enhance antigen presentation by inducing cellular immunogenic death(ICD),thereby promoting the activation of cytotoxic T lymphocytes To activate the body’s immune response;combined with chemotherapeutic drugs that have a special effect on the tumor microenvironment to enhance the immunotherapy effect,such as sunitinib(Sunitinib,SUN)has anti-angiogenesis,inhibits the growth of cancer-related fibroblasts and reduces tumor microenvironment The level of immunosuppressive cells in the environment,etc.Blocking PD-1 and its ligand PD-L1 can prevent tumors from escaping from the body’s immune killing,activate T cells,and improve the body’s anti-tumor immunity.In this paper,a therapeutic system of PTX/SUN co-delivered polymer micelles combined with a PD-1 was designed to evaluate its anti-tumor effect in TNBC.(1)In this paper,the self-assembly method was used to prepare paclitaxel and sunitinib co-delivery micelles(P/S micelle),and the particle size was 134.5±1.4 nm,the PDI was 0.127±0.06,and the potential was-The stable drug-loaded micelles of47.43±0.14 m V have the characteristics of sequential drug release.The large amount of SUN released in the early stage improves the microenvironment of the tumor site,and then cooperates with the continuous release of PTX to induce the production of tumor cell ICD.(2)With 4T1 cells as the research object,P/S micelle was evaluated at the cell level.The amphiphilic copolymer SMA selected in this paper has good biocompatibility.P/S micelle not only has a strong anti-tumor effect,but also promotes tumor cell apoptosis,releases related damage factors(DAMPs)and induces the maturation of DC cells,causing tumor cells to produce ICD,which in turn produces effective immune activation.(3)Construct 4T1 tumor-bearing mouse model,and evaluate P/S micelle combined with a PD-1 at animal level.Compared with other treatment groups,the P/S micelle+a PD-1 group has a significant anti-tumor growth effect,and its tumor inhibition rate reached 63.23%.Through immunofluorescence staining and flow cytometric analysis of mouse tumor tissues in each treatment group,it can be seen that the P/S micelle+a PD-1 group can more strongly induce tumor cell apoptosis,promote tumor cells to produce ICD,and then Induce the maturation of DC cells.Through flow cytometry analysis of the cell subsets and the proportion of positive cells in tumor tissues,it can be seen that P/S micelle+a PD-1 significantly inhibited the levels of MDSC and Treg cells in tumor tissues,and increased CD4,CD8 and NK cells in tumor tissues.The immunohistochemical section shows that P/S micelle +a PD-1 can also inhibit tumor angiogenesis and the proliferation of cancer-related fibroblasts.