Construction And Application Of Near-Infrared Treatment Strategy Based On Tumor Microenvironment Regulation

The incidence of cancer has continued to increase over the past few decades.Although several emerging oncology therapies have made clinical progress,solid tumor treatment still faces challenges such as poor efficacy,low patient response rate and large toxic side effects.The tumor microenvironment(TME)plays a critical role in solid tumor treatment,which not only impeding the anti-cancer drug infiltration,reducing drug efficacy,but also inhibiting immune cell activity.Therefore,the regulation of TME is the key to improving the tumor efficacy.In recent years,the TME regulation strategy based on near-infrared(NIR)diagnosis and treatment integrated nanomaterials has shown great advantages in enhancing tumor efficacy,which can precisely regulate TME under the guidance of NIR fluorescence imaging and synergically promote synergistic efficacy.However,the current nanoregulatory strategy of TME still faces challenges in terms of targeting efficiency,specificity and regulatory efficiency.Therefore,we have constructed a series of new NIR nanodiagnosis and treatment strategies based on TME regulation to achieve efficient tumor treatment.All the work was divided into 6 chaptersChapter 1:The properties of TME,domestic and international tumor treatment strategies,the development of NIR nanomaterials in diagnostic and therapeutic fields and biosafety analysis were reviewed.Chapter 2:Multifunctional nanocatalysts(BCG NPs)based on Cu-doped black phosphorus quantum dots and glucose oxidase(GOD)were constructed,which could exert chemodynamic therapy(CDT)effects by Cu+-catalyzed Fenton-like reactions,and utilize GOD to consume glucose in TME increase the H2O2 content in situ to amplify oxidative stress to enhance CDT.In addition,the photothermal conversion ability of black phosphorus quantum dots could be utilized to exert the synergistic effect of photothermal therapy(PTT)and CDT with the assistance of NIR laser,and further improve the efficacy.Chapter 3:Multifunctional diagnostic and therapeutic nanoprobe(AMG@CM)was obtained by loading Ag2S quantum dots and GOD on the surface of MnO2 nanosheets and camouflaged by tumor cell membranes.Tumor cell membrane camouflage allowed AMG@CM to evade immune clearance and target tumors efficiently.Under the effect of high glutathione(GSH)concentration at TME,MnO2 was decomposed and released Mn2+,which restores the NIR-Ⅱ fluorescence of the quenched Ag2S quantum dots.At the same time,the released Mn2+could be used for magnetic resonance imaging(MRI)to achieve GSH-responsive dual-modal "TumOn" imaging.The GSH-triggered release of Mn2+ could exert CDT effects,and the GOD in the probe can enhance the CDT effects by boosting the H2O2 content in TME in situ.Based on this,the PTT function of AMG@CM could be combined to achieve synergistic PTT/CDT treatment with TME-specific response.Chapter 4:A multifunctional nanocatalyst(APHA@CM)was constructed to enhance the therapeutic effect of CAR T cells on solid tumors by regulating TME,and a CAR T cell membrane modification strategy was developed to improve the tumor targeting efficiency of APHA@CM.APHA@CM not only has excellent multimodal imaging performance such as NIR-Ⅱ fluorescence,CT,photoacoustics,etc.,but also has oxidase-like activity,which can inhibit tumor glycolytic metabolism,reduce lactic acid efflux,create TME suitable for the survival of CAR T cells,and promote the activation of CAR T cells in tumors.In addition,APHA@CM-mediated synergistic therapy of PTT and sonodynamic therapy(SDT)can induce immunogenic cell death of tumor cells,reshape the tumor immunosuppressive microenvironment,and further promote the efficacy of CAR T cells on solid tumors.This strategy can not only completely ablate the tumor,but also form a long-term immune memory effect,inhibit the metastasis and recurrence of the tumor.Chapter 5:A novel NIR-Ⅱ fluorescence imaging-guided electroimmunotherapy was developed.The therapy used the electrostatic breakdown pulse current generated by the flexible fabric triboelectric nanogenerator(TENG)to cause immunogenic cell death of tumor cells,while inducing cytokines and immune cells to accumulate to the tumor site through the blood circulation system,effectively activating the body’s T cell-mediated anti-tumor immune response,further inhibiting tumor growth,and prolonging the survival of tumor-bearing mice.Chapter 6:A summary of all the work and an outlook on TME modulation and tumor synergistic therapy.