Construction Of Porphyrin-based Metal-organic Frameworks To Enhance Synergistic Photodynamic-Immunotherapy For Tumor

Immunotherapy has been proved to be one of the most potential therapeutic strategies after surgical operation,chemotherapy,photodynamic therapy,etc.The purpose of immunotherapy is to suppress tumors by regulating the body’s autoimmune system,activating immune cells to recognize and eliminate tumor cells,so as to inhibit tumor progression.However,as a single therapeutic in the clinical the treatment effect of immunotherapy,partly due to ineffective antigen presentation and insufficient activation of host immune systems.In order to enhance the intensity of immune response as well as acquire more competitive therapeutic efficacy,it is also required to make tumor cells possess good immunogenicity.Consequently,the combination of local therapy with immunotherapy that can produce immunogenic cell death could efficiently and specifically kill tumor cells.Numerous studies have shown that topical photodynamic therapy may lead to the immunogenic death of tumor cells,which will release a large amount of tumor-associated antigens and immune cytokines,antigen-presenting cells will uptake tumor-associated antigens,and abundant immune cells will be recruited and activated to enter tumor sites,primarily stimulate the anti-tumor immune response in the meantime interact with the immune response.The combination of photodynamic therapy and immunotherapy is expected to increase the therapeutic effect.Photodynamic therapy induces immunogenic death of tumor cells.The dying tumor cells release tumor-associated antigens and danger-associated molecular patterns to activate antigen-presenting cells.Meanwhile,immunomodulators reverse the tumor immunosuppressive microenvironment and activate immune cells to efficiently and specifically kill tumor cells.It might be a significant strategy to relieve tumor microenvironment immunosuppression and break tumor immune tolerance by combining two therapeutic means.Presently,NMOFs with excellent chemical stability,structural adjustability and good biocompatibility in vivo as new type materials for drug delivery systems have attracted great attentions.The antitumor remedy efficiency of NMOFs is affected by its own physical and chemical properties,such as size,shape,surface charge,etc.Correspondingly,the design and construction of a reasonably versatile NMOF may significantly prolong the circulation time,expand tumor enrichment and improve anti-tumor effects.In this thesis,we constructed two kinds of porphyrin-based metal-organic frameworks to enhance tumor synergistic photodynamic-immunotherapy for tumor,the details are as follows:（1）To investigate the application of NMOF materials in photodynamic and immunotherapy,we prepared two-dimensional nano-sheet material Cu-TCPP through the coordination of Cu with the photosensitizer（TCPP 5,10,15,20-tetrakis（4-carboxyphenyl）porphyrin）.The obtained results showed that Cu-TCPP could be enriched in tumor tissue through the EPR effect,and be effectively uptake by tumor cells Under light illumination,Cu-TCPP could effectively generate singlet oxygen to kill tumor cells,induce tumor cell production of ICD,and alleviate immunosuppression of tumor microenvironment.（2）On the basis of the above system,the multifunctional nanocomplex HA-PMTG@MOF^Fe-TCPPwas successfully constructed.The core of the nanocomposite was an iron porphyrin metal organic framework,and was encapsulated by amphiphilic block copolymer（HA-b-P（1-DMT-co-L-Glu））.The experimental results showed that the introduction of hyaluronic acid could not only target 4T1 cells but also improve the stability and dispersity of Fe-TCPP.Under cellular acidic and high glutathione（GSH）content,Fe³⁺and GSH could undergo oxidation-reduction reaction to release Fe³⁺and TCPP and enhance the efficacy of photodynamic therapy light irradiation,the tumor suppression rate of HA-PMTG@MOF^Fe-TCPPreached to 85.3%.HA-PMTG@MOF^Fe-TCPPcould induce tumor cells to produce ICD,express high level of damage-associated molecular patterns（DAMPs）,activate dendritic cell（DC）and accelerate T cell proliferation and activation.In addition,HA-PMTG@MOF^Fe-TCPPinduced an increased level of antitumor cytokines,such as interleukin-2（IL-2）,and interleukin-12（IL-12）,to improve the tumor microenvironment and stimulate the occurrence of an anti-tumor immune response.The released indoleamine 2,3-dioxygenase（IDO enzyme）inhibitor dextro-1-methyl tryptophan（1-DMT）could enter the tumor microenvironment and reverse the immunosuppression microenvironment to enhance the immune response of CD4⁺T and CD8⁺T cells and inhibit the proliferation of immunoregulatory T cells（Tregs）as well as the growth of breast cancer.The results confirmed that the combination of PDT and immunotherapy can effectively inhibit tumor growth,outlining a potential clinical application.