Multiple Stimulus-responsive Nano-drug Delivery System For Inhibitin IDO Pathway And Enhancing Tumor Photodynamic Immunotherapy

The morbidity and mortality of malignant tumors in China are on the rise year by year.The current clinical treatment methods are not ideal for anti-tumor,traditional methods of tumor treatment are surgery,radiotherapy and chemotherapy.Studies have shown that photodynamic therapy(PDT)can activates the anti-tumor immune response,and recruits cytotoxic T cells(CTLs)to migrate and infiltrate into tumor tissues.However,how to accurately deliver drugs to the lesion site is still a major reason for limiting tumor immunotherapy,and PDT activation of immune response can also be blocked by the immunosuppressive microenvironment of tumor tissue.In this paper,we designed and synthesized amphiphilic polymer precursors for tumor microenvironmental response,self-assembled into multiple stimulus-responsive nanoparticles that respond to MMP-2/9,intracellular lysosomal acid and glutathione in tumor tissue.Nanoparticles uses EPR effect to passively target tumor tissues,and makes a responding to the overexpressed MMP-2/9 of tumor microenvironment and then remain in the tumor microenvironment by removed PEG shell and was uptaken by tumor cells;then makes responding to lysosomal acid and GSH of tumor cells to release PPa and NLG919.PDT activates the anti-tumor immune response,NLG919 inhibits the activity of IDO,and reinstates the CTLs activity in the infiltrating tumor microenvironment,thereby killing tumor cells and enhancing the PDT-induced immune response.Multi-stimuli responsive nanosized drug delivery system was fully verified by in vitro simulation experiment and in vivo experiment.The results showed that photosensitizer and NLG919 were effectively accumulated in tumor site.In CT26 cancer models,the tumor inhibition effect was significant,and the abscopal model also showed an ideal effect.The above experimental results show that the multi-stimuli responsive nanosized drug delivery system makes full use of characteristics of tumor tissue and selected kills tumor cells,and makes achievements in anti-tumor immunotherapy.