Rational Design Of Nanomaterials For Cacner Therapy: Nano-tumor Immunotherapy

Tumor is still one of the main challenges to human health.From traditional surgical intervention,radiotherapy,chemothearapy to the developing immunotherapy,tumor immunotherapy is known as the most efficient method.But with the limitation of the heterogeneity and immune suppression of tumor,tumor immunotherapy is only benefit for part of the patients.Nanotechnology as one of the emerging technologies,has been made significant progress in biomedicine field,especially in tumor therapy.Combining nanotechnology and tumor immunotherapy together,will surmount the barriers of immunotherapy and promote the development of immunotherapy.Although more and more studies have explored the application of nanotechnology in tumor therapies,most of studies focused on the nano-delivery,there were less reports for nano-tumor immunotherapy in ture sense.This dissertation focused on two nano-tumor immunotherapies,will be regarded as the fundamental studies for subsequent tumor immunotherapy.Construction of one nanosystem used for tumor therapy(Mn₃O₄@Au-ds DNA/DOX)by combining the STING(stimulator of interferon genes)-mediated innate immune system and chemotherapy together.In this study we chose ds DNA as the STING stimulator,STING-mediated innate immune system was different from the traditional nuclei acid(like Cp G)-mediated immune system;Conjugating the gold nanoparticles and ds DNA together(Au-ds DNA)for stimulating STING pathway surmounted the chanllenges of synthesis and delievery STING stimulator,and this conjugation was the innovation point;Au-ds DNA could assemble with Mn₃O₄via a noncovalent attachment strategy;Synegeristic effect was obtained by combining Au-ds DNA mediated immunotherapy and DOX-mediated chemotherapy together;Based on the activation of immune system and synergeristic effect of chemical drug,our construction successfully applied in melanoma and breast tumor bearing mice models.In addition to the immune activation and syngeristic effect with chemical drug,our design exhibited more function such as imaging and hypoxia relief.Design and develop one nanosystem for nano-tumor immunotherapy based on the properties of nanoparticles.Immune activation should be obey the cycle of immunity,lack the exposure of tumor antigen and polarization of immunosuppressed cells due to tumor microenvironment(especially the hypoxic microenvironment)are the main reasons for tumor immunosuppression.To tackle these limitation together,constructing one nanosystem applied for tumor immunotherapy both in enhancing tumor antigen exposure and hypoxia relief,this system was based on the properties of nanoparticles own and without extra theraptical drug.In this study we chose the gold nanorod(Au NR)as the element for tumor antigen exposure;Mn O₂ as the element of hypoxia relief due to its capacity of decomposing H₂O₂ into O₂;these two elements combined together by good-biocompatible molecule BSA(bovine serum albumin)and formed Au NR@BSA/Mn O₂ for tumor immunotherapy.Au NR mediated-photothermal therapy(PTT)could cause the death of tumor cells,and these dying tumor cells could release the antigen,then activate the immune system;Mn O₂ could decompose the H₂O₂ into O₂ which could modulate the hypoxia microenvironment,then promote the polarization of immunosuppressed cells to immunofriendly ones,meanwhile enhance the immunotherapy;these two elements combined together into one nanosystem and performed good biocompatibility after intravenous injection;Combination with immune checkpoint therapy this nanosystem exhibited great distant effect and anti-metastasis ability due to immue activation and enhancement;Multi-imaging function was exhibited due to the elements of the designed nanoparticles.This study could be regarded as the nano-tumor immunotherapy in the ture sense,could be as the fundamental study for the later nano-immuotherapy.