Research On The Construction Of Nano-medicine And Its Anti-tumor Activity Based On The Characteristics Of Tumor Microenvironment

Cancer,also called malignant tumor,is one of the important diseases that threaten human health.In addition to tumor cells in solid tumors,there are a large number of fibroblasts,myofibroblasts,neuroendocrine cells,adipocytes,immune cells and inflammatory cells,blood and lymphatic network,and extracellular matrix(ECM),which together constitute the tumor Microenvironment.The tumor microenvironment has unique physiological and biochemical properties,including interstitial hypertension,vascular system abnormalities,abundant proteases and hyaluronic acid,low p H acidic environment,and hypoxia.Recent studies have shown that the tumor microenvironment is closely related to tumor proliferation,invasion and metastasis.The design of tumor therapeutic drugs based on the characteristics of tumor microenvironment has become the focus of research.Compared with traditional tumor treatment methods,light-triggered tumor treatment has the advantages of selective tumor treatment and effectively reduces the side effects of treatment on normal tissues.Photodynamic therapy(PDT)and photothermal therapy(PTT)are the two most important light-triggered tumor treatments.The efficacy of PDT depends on the active oxygen produced by photosensitizers that are enriched in the tumor site by light.The treatment of PTT relies on the effect of light-to-heat conversion,which uses heat sensitizers to convert light to heat and kill tumors.In this thesis,based on the purpose of enhancing PDT and PTT,according to the characteristics of tumor microenvironment,two nano-drug systems are designed to carry out anti-tumor research in vivo and in vitro.The specific content and results are as follows:(1)A disulfide-linked hyaluronic acid-coated photothermal material-palladium nanosheets(Pd NSs)was used to synthesize a composite material(Pd NSs @ HA-ssHA).By binding the HA of Pd NSs surface to the highly expressed CD44 receptor on the surface of tumor cells,the tumor cell uptake ability of nanomedicine was improved.Photothermal nanomaterials Pd NSs have excellent thermal cycling effects and small size nanomaterials have good biocompatibility.In vitro experiments have shown that HA coating can significantly improve the tumor community effect of Pd NSs,effectively increase the PTT antitumor activity of Pd NSs,and lay the foundation for the design of tumor therapeutic drugs based on the characteristics of tumor microenvironment.(2)Pass the photosensitizer zinc phthalocyanine(Zn Pc),gas carbon monoxide(CO)donor pentacarbon manganese bromide(I)(COMn)and tumor-associated fiber(CAF)inhibitor losartan potassium(Dup)Co-loaded in the mesoporous silica nanoparticles(MSNs),then the cross-linked hyaluronic acid(HA)gel shell was coated on the surface of the MSNs to form ZDCMH NPs.After injecting into the blood of mice through tail vein,nano-drugs achieve high-efficiency enrichment in tumor tissues through the high permeability and retention effect(EPR)of solid tumors and the targeting effect of hyaluronic acid to tumor surface high CD44 receptors.Subsequently,the HA enzyme in ECM degrades the HA gel shell,triggering the release of the encapsulated drug.After light source irradiation,Zn Pc exerts PDT activity to generate a large amount of reactive oxygen species(ROS),induces COMn to release CO,expands tumor vessels,strengthens the EPR effect,and promotes the accumulation of ZDCMH NP in tumor tissues.In addition,the released Dup can inhibit the CAF activity,reduce the concentration of collagen fibers in TME,promote the deep penetration of ZDCMH NPs in solid tumors,and help Zn Pc to exert better PDT effect.At the same time,the use of Zn Pc fluorescence imaging in nanocomposite drugs and NMR imaging of Mn ions in COMn provides the basis for detecting drug distribution in vivo.Experimental studies in vitro and in vivo show that ZDCMH NPs,a multifunctional compound drug that destroys TME based on multiple strategies,has achieved significant antitumor activity.