Study On The Preparation Of Two-dimensional Transition Metal Nanomaterials And Their Synergistic Cancer Treatment Performance

Malignant tumors are still one of the deadliest diseases threatening human health.At present,due to the diversity,complexity and heterogeneity of tumors,single therapy usually can not completely ablate tumors.In order to alleviate the current problems of monotherapy,the dual-mode or multi-mode treatment can be integrated into a system to maximize the bioavailability of the drug,and the excellent synergistic effects can be achieved.Compared with other materials,two-dimensional nanomaterials show unique biomedical properties due to their specific structure and morphology.However,there are few reports on the ablation of deep tumors and the construction of multifunctional two-dimensional nanomaterials for the tumor microenvironment（TME）-specific therapy.Therefore,the construction of new two-dimensional nanomaterials to achieve TME-specific synergy therapy is expected to promote the research of high-efficiency and precise cancer treatment.Two-dimensional layered double hydroxides（LDHs）have been widely used in the field of biomedicine due to their characteristics of topological structure transformation,the adjustability of the main laminate and good biocompatibility.In this thesis,based on the excellent properties of LDHs,two two-dimensional nanomaterials with TME stimulus response function were synthesized and used for tumor synergistic therapy.Two-dimensional CuFe₂S₃ and CuAl-LDH nanosheets were synthesized through the transformation of topology and the adjustable denaturation of the main layer.The photothermal performance of the prepared two-dimensional nanomaterials in NIR-II,Fenton-like catalytic performance,catalytic CuAAC performance and the versatility of the material response to TME overexpression were explored.Construct NIR-Ⅱ PTT and CDT as well as CDT and bioorthogonal chemistry combination therapy to achieve a good synergistic therapeutic effect.The major research contents of this paper are shown below:1.The preparation of two-dimensional CuFe₂S₃-PEG nanosheets and their photothermal/chemodynamic propertiesThe "bottom-up" preparation method was adopted to synthesize CuFe-LDH nanosheets,ultrathin CuFe₂S₃ nanosheets were prepared by sulfurization of CuFe-LDH nanosheets via a simple hydrothermal treatment.The ultrathin CuFe₂S₃ nanosheets have a lateral size of～63 nm and an average thickness of～1.5 nm.After modification with polyethylene glycol（PEG）,CuFe₂S₃-PEG nanosheets were obtained.The CuFe₂S₃-PEG show excellent NIR-Ⅱ absorption ability and photothermal conversion efficiency（η）is～55.86%under irradiation by a 1064 nm laser.Moreover,the overproduced glutathione in the tumor microenvironment can react with CuFe₂S₃-PEG nanosheets to release Fe²⁺ and Cu⁺,thus activating Fenton reaction to efficiently produce hydroxyl radicals（·OH）.The combination index（CI）<0.6 calculated by in vitro experiments proves that CuFe₂S₃-PEG nanosheets have an excellent CDT/PTT synergistic therapeutic effect.In vivo tests,CuFe₂S₃-PEG has significant CDT/PTT synergistic antitumor performance.This work provides an effective way to integrate NIR-Ⅱ PTT and PTT/GSH responsive CDT within the same nanoplatform for high-efficiency tumor-specific therapy.2.Synthesis of CuAl-LDH nanosheets and their like-Fenton/CuAAC catalytic performanceTwo-dimensional CuAl-LDH nanosheets were synthesized by the"bottom up" method.The depletion of reducing GSH overexpressed in TME by CuAl-LDH nanosheets was explored.A series of characterizations proved the consumption of GSH and the generation of Cu⁺.The CuAAC reaction of coumarin containing azide group and phenylacetylene was catalyzed after the reaction of CuAL-LDH with GSH,which indicated that CuAl LDH had excellent catalytic performance in CuAAC reaction and could be used to synthesize drug analogues for cancer treatment.Subsequently,the catalytic performance of like-Fenton reaction was tested,showing that a slightly acidic condition is benefit to ·OH generation.In addition,in vitro experiments,it was tested that CuAl-LDH nanosheets have good biocompatibility and good ability to catalyze the CuAAC reaction,which provides a basis for in-situ synthesis of cancer therapeutic drugs in vivo for chemotherapy/chemodynamic synergistic therapy.In summary,based on the structural characteristics of the topological transformation of LDHs and the adjustable characteristics of the metal elements of the main layer,this paper synthesizes two-dimensional nanomaterials that integrates a multi-functional treatment mode.The prepared nanomaterials have excellent therapeutic properties and good biocompatibility,and play an important role in guiding the development of two-dimensional nanomaterials to achieve TME-specific response to the synergistic therapy.