| Inducing effective immune response is essential in the treatment and protection of diseases.However,the commonly used therapeutic drugs or immunomodulators in immunotherapy are lack of specificity and have low bioavailability.While some antigenic molecules have poor in vivo stability and are difficult to effectively reach target cells.In recent years,nano drug delivery systems have been developed for the efficient delivery of immunotherapeutic molecules to enhance the accumulation of drugs to target cells,thereby helping drugs to elicit effective immune responses to improve therapeutic efficacy.Based on this,my doctoral research is devoted to the development of multifunctional nanocarriers with excellent biocompatibility for the loading and precise delivery of therapeutics and vaccines,as well as carefully studying the behavior of enhancing immune responses,aiming to provide new strategies for tumor immunotherapy and viral prevention.The main researches are summarized as follows:1.The high expression of indoleamine 2,3-dioxygenase 1(IDO1)is one of the main reasons of tumor immunosuppression.When combined with chemotherapeutic drugs,IDO inhibitors can effectively reverse the immunosuppressive tumor microenvironment.Inspired by the multifunctional drug-loading capacity and excellent tumor targeting of liposome,we constructed an oxaliplatin prodrug liposome and encapsulated the alkyl modified IDO inhibitor NLG919 in it,realizing the efficient delivery of chemotherapeutic drugs and immunomodulatory molecules to tumors,and enhancing the bioavailability of oxaliplatin and NLG919.The obtained aNLG/Oxa(Ⅳ)-Lip can responsively release oxaliplatin in the reducing environment of the cytoplasm to trigger immunogenic death(ICD)of cancer cells,which significantly reduces the toxic and side effects.The tumor immunosuppressive microenvironment can also be reversed by NLG919-mediated inhibition of IDO1.Therefore,the chemo-immunotherapy synergistic effect was achieved in mouse subcutaneous and orthotopic colorectal cancer models.2.Combining multiple treatments is also an effective way to improve therapeutic efficacy.We prepared a covalent organic polymer drug delivery platform,THPP-Oxa(Ⅳ)-PEG,by coupling the constructed oxaliplatin prodrug and the sonosensitizer Meso-tetrakis(p-hydroxyphenyl)porphyrin(THPP).This strategy enhanced the water-soluble of THPP,and realizing the effective combination of chemotherapy and sonodynamic therapy(SDT).The prepared THPP-Oxa(Ⅳ)-PEG can be cleaved in the tumor reducing microenvironment,allowing the precise release of oxaliplatin at the tumor site and inducing the immunogenic death of tumor cells.Upon ultrasound exposure,THPP can effectively generate cytotoxic reactive oxygen species(ROS),leading to effective inhibition on mouse colorectal cancer model via chemo-sonodynamic combination therapy.3.Considering local precision transdermal therapy is more suitable for the treatment of skin cancers such as melanoma than systemic drug delivery,we designed a transdermal DNA tetrahedral framework nucleic acid drug delivery system(FNAIA)which containing CpG sequences,and then loaded with the chemotherapeutic drug DOX for transdermal treatment of melanoma.Compared with free drugs,this framework nucleic acid carrier can more efficiently deliver drugs to subcutaneous tumor tissues to kill tumor cells,induce the release of antigens from dying tumor cells,and at the same time effectively stimulate the maturation of surrounding dendritic cells(DCs),thereby causing the generation of in situ vaccines and inhibiting tumor growth.When combined with α-PD-1,the systemic immune response elicited by the in situ vaccine was able to suppress both the treated tumor and the distant untreated tumor.4.Inspired by the efficient loading and delivery of immune adjuvant CpG by framework nucleic acid in previous work,we assembled antigen peptides on the framework nucleic acid immune adjuvant for novel vaccine development.First,we optimized the vaccine structure with model antigen peptide OVA323-339.With the help of adjuvant and carrier,the immunogenicity of the peptide was significantly enhanced.The rigid tetrahedral structure TH37 with the longest side length represented the best capability to activate B cells.In addition,the framework nucleic acid carrier has lower immunogenicity than the BSA carrier and can help antigen peptide cause the production of specific antibodies in mice more safely and efficiently.Afterwards,we edited S protein B cell epitope peptides on the optimal structure TH37 to construct novel coronavirus(SARS-CoV-2)prevention vaccine(TH37R-S3/S4-ORF3a-CpG).It could not only effectively produce specific neutralization antibodies,but also induce the differentiation of immune memory cells,which is expected to protect mice from SARS-CoV-2 infection in the long term.In summary,in this doctoral dissertation,we developed a variety of nano-drug delivery systems with excellent biocompatibility for the loading of therapeutic agents or vaccines,which improved their in vivo bioavailability,reduced toxic side effects and enhanced the immune responses,thus proposed new strategies for combined immunotherapy of tumors and virus prevention. |
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