Metal-Organic Framework Nano Drug Delivery System And Its Application In Colorectal Cancer Immunity Complex Therapy

Colorectal cancer(CRC)is one of the most common malignant tumors in the gastrointestinal tract,posing a serious threat to human health.Although surgery is preferred,40-50% of patients are at risk of recurrence and metastasis,after which no effective treatment is available.Tumor immunotherapy has a specific tumor-suppressive effect,which brings new hope for patients with recurrence or metastases and becomes the fourth of tumor treatment.However,the poor tumor immunogenicity and tumor immunosuppressive microenvironment limit the effect of immunotherapy.In addition,the rich tumor stroma effectively forms a physical barrier that inhibits drug penetration and better maintains the tumor immunosuppressive microenvironment.Therefore,during tumor immunotherapy,we need to regulate multiple elements of tumor immunosuppressive microenvironment formations to maximize the activation of tumor immune effect and develop new therapies for patients with metastatic CRC.The emergence of nanomaterials has revolutionized human health and is already making its mark in the field of oncology therapy.Nanomedicines could enhance drug stability,prolong drug blood half-life,tumor-targeting ability,and tumor microenvironment responsive release,which improve the effect of antitumor chemoimmunotherapy in several aspects.Therefore,a reasonably designed nanocarrier improves the drug delivery process,enhances the antitumor immune effect,and achieves the best tumor suppression effect.Based on this,the following work is carried out in this thesis:(1)Exploring metal-organic framework nano-drug delivery system combined with photothermal therapy for immunotherapy of CRC.To address the scientific problems of weak immunogenicity of tumor cells and tumor immunosuppressive microenvironment leading to poor immunotherapeutic effect,we successfully constructed iron-based multifunctional metal-organic framework nanomaterials with photothermal responsiveness and tumor targeting to realize integrated photothermal,chemotherapy,and immunotherapy as a comprehensive tumor-targeting therapy,to solve the therapeutic challenges of CRC that has lost the opportunity of surgical treatment.Firstly,we selected metal-organic framework MIL-100 for the loading of mitoxantrone hydrochloride(MTO)and masked hyaluronic acid(HA)on its surface to construct a multifunctional metal-organic framework nano-drug delivery system MMH NPs.HA not only enhances the dispersion and stability of MMH NPs but also enables them to have the tumor-targeting ability.Secondly,MTO,as an anthracycline chemotherapeutic drug,could induce immunogenic cell death(ICD)in tumor cells with photothermal properties,so MMH NPs-mediated photothermal-chemotherapy doubly enhances tumor ICD levels,activates dendritic cells(DCs)to deliver antigens to T cells,and activates tumor immune effects.In addition,combined with immune enhancers co-stimulatory signaling molecule OX40 antibody(?OX40)agonist treatment can inhibit the activity of immunosuppressive cells,reverse the tumor immunosuppressive microenvironment,promote the survival and expansion of effector T cells,and enhance the antitumor immune effect,which can produce powerful CRC treatment effects and effectively inhibit the metastasis.(2)Metformin(MET)reprograms the tumor immune microenvironment and enhance the therapeutic efficacy of the above immune complex therapy.The dense tumor stroma and collagen form a physical barrier that better maintaining the state of the tumor immunosuppressive microenvironment.To address this issue,based on previous work,we proposed a combination strategy of tumor stroma inhibition using MET and nano immunotherapy for reprogram the tumor immune microenvironment and promote chemoimmunotherapy combination therapy for CRC.In this combination,MET was first injected intraperitoneally continuously into tumor-bearing mice to disrupt the dense tumor stroma,followed by vein injection of pre-prepared multifunctional nanodrug MMH NPs to promote the accumulation of nanodrug within tumor sites,induce stronger ICD and activate the immune response to effectively inhibit the growth of CRC.More importantly,when combined with the immune enhancer ?OX40 treatment,it could synergistically against in situ CRC and enhance the immunotherapeutic effect.In conclusion,the combination strategy of MET/MMH NPs/?OX40 provides a novel and effective clinical treatment option for CRC immunotherapy.The purpose of this thesis is to explore the value of nano immunotherapy platform in the treatment of CRC and provide novel strategies for patients with metastatic CRC who are difficult to undergo surgical treatment,which holds certain clinical translation prospects.