Design, Preparation And Tumor Diagnosis And Treatment Performance Of Hollow Copper Sulfide Nanocomposite Structure

In recent years,the deficient copper sulfide(Cu2-x S)nanoparticles have attracted a lot of attention in photothermal therapy(PTT)and chemodynamic therapy(CDT)for cancer treatments,due to their unique near-infrared absorption conversion properties,high Fenton-like reactivity,and good biocompatibility.However,the limited penetration depth of near-infrared light and low endogenous H2O2 severely limit the efficacy and clinical translation of copper sulfide-based single PTT and CDT.Therefore,it is of great significance to develop a combined treatment modality of PTT/CDT and other treatment modalities to improve the tumor treatment efficiency and reduce the damage to normal tissue caused by the laser.In this thesis,starting from the content regulation and utilization of H2O2 in the tumor microenvironment,hollow copper sulfide nanoparticles(H-Cu2-x S,HC)are used as multifunctional drug carriers to load glucose oxidase(GOx)and H2O2-responsive NO gas donor L-Arginine(L-Arg)into their cavities simultaneously.A hollow copper sulfide-based multifunctional nanotherapeutic agent(H-Cu2-x S@GOx/L-Arg,HCGL)was constructed for near-infrared imaging-guided mild photothermal / chemodynamic /starvation / NO gas combined therapy.The nano-therapeutic agent exhibits satisfied tumor treatment effects and high biocompatibility both in vitro and in vivo.The successful construction of this nano-therapeutic agent provides a new strategy for the development of multimodal combined therapy for cancer treatment.The main contents of the thesis are as follows.Chapter 1: The current emerging cancer treatment methods,such as photothermal therapy,chemodynamic therapy,starvation therapy,and gas therapy in the treatment of malignant tumors,are reviewed.The application status of copper sulfide nanomaterials in the treatment of malignant tumors is summarized.The research idea of this paper is put forward.Chapter 2: HC(H-Cu2-x S)nanoparticles were successfully prepared,and then glucose oxidase(GOx)and arginine(L-Arg)were simultaneously loaded into their cavities to construct a copper sulfide-based multifunctional nanotherapeutic agent HCGL(H-Cu2-x S@GOx/L-Arg).The dispersibility,morphology,size,photothermal properties,Fenton-reaction activity,H2O2 production,H2O2-triggered NO release,and p H changes of HC nanoparticles and HCGL were detailedly investigated and discussed.Chapter 3: Based on the successful construction of HCGL nanotherapeutics,the multimodal combined therapeutic effects of HCGL both in vitro and in vivo were carefully explored.First,the cytotoxicity of HCGL to normal cells(HUVEC-human umbilical vein endothelial cells)and cancer cells(4T1-mouse-derived breast cancer cells)was investigated,and a safe and effective dose was determined.As for in intro study,the killing effect and mechanism of HCGL on cells were qualitatively and quantitatively characterized by MTT method and fluorescent staining method.As for in vivo study,a 4T1 mouse breast cancer model was constructed and HCGL was injected into the mice through tail vein injection.The biosafety,near-infrared thermal imaging performance and tumor inhibition effect of HCGL were evaluated in detail.The experimental results showed that the HCGL has good biocompatibility,near-infrared thermal imaging effect,and mild photothermal / chemodynamic /starvation / NO gas combined antitumor activity.Chapter 4: The preparation and characterization of the multifunctional theranostic agent constructed by HCGL and its applications both in vitro and in vivo are summarized.The insufficiency is discussed,and further application research in the field of biomedicine has been prospected.