Study On The Targeted And Specific Therapy Of Solid Tumor With Engineered Macrophage Vector Polarization Activated Nano Prodrug

The lack of clear immunotherapeutic targets and severe side effects caused by non-specific systemic chemotherapy are serious challenges for clinical drug therapy of triple-negative breast cancer and other solid tumors.Due to the high toxicity,low immunogenicity and easy metastasis of the tumor,traditional chemotherapy and emerging immunotherapies have a poor prognosis in the clinical treatment of solid tumor.Therefore,we developed an intelligent prodrug targeted delivery-activation system based on macrophages.Macrophages were genetically modified in vitro using tyrosinase plasmid regulated by arginase 1 promoter.With the ability of specific expression of exogenous tyrosinase in tumor microenvironment,MSNs loaded with APAP prodrug was loaded into the engineered Macrophages through endocytosis and follow it with targeting into the tumor microenvironment.In the immunosuppressive tumor microenvironment of solid tumor,engineered macrophages will gradually become M2-type polarized,and this polarization process is accompanied by the activation of arginase 1 promoter.At this time,exogenous plasmids begin to express tyrosinase in large quantities.With the expression of Tyrosinase activated by TAM,when the expression level of tyrosinase in TAM increases gradually,APAP nano-prodrug that follows macrophages to the tumor microenvironment catalyzes to highly toxic chemotherapy drug AOBQ,so as to perform in situ and metastatic chemotherapy for solid tumors.This strategy has demonstrated excellent therapeutic efficacy and good biosafety for 4T1 triple negative breast cancer models in vitro and in vivo.Therefore,the smart prodrug targeted delivery-activation system can be used as a potential clinical treatment alternative for triple negative breast cancer and cancers with similar tumor characteristics.