| Tumor has its unique characteristics,such as vascular abnormalities,hypoxia,slightly acidic pH,high oxidation,protein-rich extracellular matrix and immunosuppressive environments compared with the normal tissues.Large numbers of studies have shown that the special tumor microenvironment facilitates the development and metastasis,and makes it antagonistic to some treatments.Therefore,the strategies of modulation tumor microenvironment to enhance the therapeutic effect have been widely investigated.At the same time,monotherapy strategy often makes the tumors resistant to the treatments,and increases the risk of tumor metastasis or recurrence.Therefore,we designed multiple responsive nanocarriers by combination of various therapy strategies,especially immunotherapy,to modulate the tumor microenvironment for cancer therapy.The main research contents and conclusions of this paper are divided into the following three parts:1st Chapter:The unique tumor microenvironments(TME)characteristic of severe hypoxia,overexpressed intracellular glutathione(GSH),and elevated hydrogen peroxide(H2O2)concentration limit the anticancer effect by monotherapy.In this report,glucose oxidase(GOx)-encapsulated hollow mesoporous Co9S8 nanoreactors are constructed with the coverage of polyphenol diblock polymers consisting of poly(oligo(ethylene glycol)methacrylate)and dopamine moieties-containing methacrylate,which are termed as GOx@PCoS.After intravenous injection,tumor accumulation,and cellular uptake,GOx@PCoS deplete GSH by Co3+ ions.GOx inside the nanoreactors produce H2O2 via oxidation of glucose to enhance ·OH-based chemodynamic therapy(CDT)through Fenton-like reaction under the catalysis of Co2+.Moreover,Co3+ ions possess catalase activity to catalyze production of O2 from H2O2 to relieve tumor hypoxia.Upon 808 nm laser irradiation,GOx@PCoS exhibit photothermal and photodynamic effects with a high photothermal conversion efficiency(45.06%)and production capacity of toxic superoxide anion(·O2-)for photothermal therapy(PTT)and photodynamic therapy(PDT).The synergetic antitumor effects can be realized by combined CDT,GSH depletion,starvation therapy,PTT,and PDT.Notably,GOx@PCoS can also be used as a magnetic resonance imaging contrast agent to monitor the antitumor performance.Thus,GOx@PCoS show great potentials to effectively modulate TEM and perform synergistic multimode therapy.2nd Chapter:Immunotherapeutic efficacy of tumors based on immune checkpoint blockade(ICB)therapy was frequently limited by immunosuppressive tumor microenvironment and cross-reactivity with normal tissues.Herein,we develop the reactive oxygen species(ROS)-responsive nanocomplexes with the function of ROS production for delivery and triggered release of anti-mouse programmed death ligand 1 antibody(αPDL1)and glucose oxidase(GOx).GOx and aPDL1 were complexed with oligomerized(-)-epigallocatechin-3-O-gallate(OEGCG),which were followed by chelation with Fe3+ and coverage of the ROS-responsive block copolymer,POEGMA-b-PTKDOPA,consisting of poly(oligo(ethylene glycol)methacrylate)(POEGMA)and the block with thioketal bonds-linked dopamine moieties(PTKDOPA)as the side chains.After intravenous injection,the nanocomplexes show prolonged circulation in blood stream with half-life of 8.72 h and efficient tumor accumulation.At the tumor sites,GOx inside the nanocomplexes can produce H2O2 via oxidation of glucose for Fenton reaction to generate hydroxyl radicals(·OH)which further trigger the release of the protein cargos through ROS-responsive cleavage of thioketal bonds.The released GOx improves the production efficiency of ·OH to kill cancer cells for release of tumor-associated antigens via chemodynamic therapy(CDT).The enhanced immunogenic cell death(ICD)can activate the immunosuppressive tumor microenvironment and improve the immunotherapy effect of the released aPDL1,which significantly suppress the primary and metastatic tumors.Thus,the nanocomplexes with Fenton reaction-triggered protein release show great potentials to improve the immunotherapeutic efficacy of ICB via the combination with CDT.3rd Chapter:The restricted tumor-infiltrating lymphocytes(TILs)in the tumor microenvironment significantly limited the cancer immunotherapy effect.Stimulator of interferon genes(STING)agonists can efficiently activate the intracellular STING pathway that promote the production of Ⅰ-type interferons(IFNs)and other cytokines.Type-Ⅰ IFNs selectively stimulate antigen-presenting cells(e.g.dendritic cells(DCs)),which in turn prime and activate tumor-antigen-specific T cells.Moreover,the activation of the STING pathway in tumor cells can lead to natural killer(NK)cells infiltrating the tumor and mobilizing an antitumor response.Herein,we constructed a biodegradable thermo-responsive hydrogel with synergistic effect of STING agonist(SR717)and immune checkpoint inhibitor(aPDL1)for the treatment of breast cancers.The thermo-responsive degradable amphiphilic polymer based on PNIPAM-b-PLA-b-PEG-b-PLA-b-PNIPAM could form hydrogels at physiological temperature coloaded with αPDL1 and redox-responsive SR717 linked polyamidoamine(PAMAM)dendrimers(PAMAM-SS-SR).After the hydrogel was injected into the tumor tissue,the encapsulated aPDLl and dendrimers were gradually released into the tumor microenvironment via polymer hydrolysis.The STING pathway was activated more efficiently by the enhanced endocytosis capacity and GSH trigged release of the PAMAM-SS-SR.Thus,the immunosuppressive microenvironment was modulated via the released cytokines,thereby enhancing the immune response.Moreover,the released aPDL1 blocked programmed cell death ligand 1(PDL1)on the surface of tumor cells to improve the immunotherapy effect by enhanced T cells recognition,which significantly suppress the primary and metastatic tumors.Thus,this biodegradable two-phase releasing thermo-responsive hydrogel,synergistic with STING pathway activation and ICB,provides a new idea for construction of tumor microenvironment modulation nanocarriers. |
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