Research On Environment-responsive Self-assembled Nanomedicine And Antigen-inorganic Hybrid Microparticle Vaccine For Tumor Immunotherapy

Cancer is still one of the main causes of death.Traditional tumor treatment approaches include surgery,chemotherapy and radiotherapy.Cancer immunotherapies have demonstrated promising clinical responses in recent years and provide a new strategy against cancer.However,there are still many challenging concerns that remain to be addressed with current cancer immunotherapy and it is necessary to further improve the efficacy of cancer immunotherapy.In this study,we developed two novel formulations of tumor microenvironment responsive particles as drug delivery system for cancer immunotherapy.which may have a great potential for the more effective therapy of cancers.Part ?:Here,a pH-responsive antigen-inorganic hybrid micro particle as a novel vaccine carrier was developed.Model antigen ovalbumin(OVA)-copper(?)sulfate hybrid vaccines(OVA-Cu-HVs)were mildly and facilely constructed through a biomimetic mineralization process.OVA-Cu-HVs can release OVA in a pH-responsive behavior and promote cytosolic release of antigen to enhance antigen cross-presentation.Immunization with OVA-Cu-HVs promoted the maturation of dendritic cells in draining lymph nodes,induced robust antigen-specific T lymphocyte response.and inhibited tumor growth in vivo.In addition.OVA-Cu-HVs were efficacious after being stored for 4 weeks at room temperature and are expected to simplify vaccine storage and lower the cost of cold storage for transportation.Part ?:Here,a tumor microenvironment-responsive therapeutic peptide-conjugated prodrug nanoparticle was developed for enhanced tumor penetration and synergistic antitumor effects of chemotherapy and immune checkpoint blockade therapy.The prodrug nanoparticle(?140 nm)is composed of a short D-peptide antagonist of PD-L1(DPPA)conjugated doxorubicin(DOX)prodrug and a PEGylated DOX prodrug,which can dissociate into small DOX nanoparticles(<30 nm)and release DPPA antagonist in tumor microenvironment.It is demonstrated that co-delivery of DOX and DPPA antagonist directly killed tumor cells.promoted the tumor-infiltrating cytotoxic T lymphocytes,reduced the tumor-infiltrating regulatory T cells and elicited a long-term immune memory effect to prevent tumor recurrence and metastasis.This tumor microenvironment-responsive prodrug nanoparticle holds promise as a co-delivery nanoplatform for the improved chemoimmunotherapy of solid tumors.In summary,we have developed two novel formulations of tumor microenvironment responsive particles as drug delivery system for improving cancer immunotherapy.OVA-Cu-HVs can improve the room temperature stability of the vaccine and achieve the cytoplasmic delivery of the antigen,promote the MHC-I antigen presentation to enhance the killing effect of CD8+ T lymphocytes and improve the anti-tumor efficacy.The tumor microenvironment-responsive PEG/DPPA peptide-doxorubicin co-loaded nanoparticles offers a new strategy for future applications of nanomedicine to achieve deeper tumor penetration and better chemo-immune checkpoint blockade therapeutic effect.