Construction Of Metal-organic Complex-based Nano Drug Delivery Systems For Combined Chemodynamic-chemotherapy Anti-cancer Therapy

New strategies have been developed in the treatment of cancer,such as phototherapy,immunotherapy,radiotherapy and chemodynamic therapy,which can be effectively combined with conventional therapies to further improve the efficacy of cancer therapy.Among them,Chemodynamic therapy（CDT）has the advantages of being less toxic,easy to administer and does not create tumour resistance.The main mechanism of CDT is to kill cancer cells by converting intracellular overexpressed H₂O₂ into highly toxic·OH through Fenton or Fenton-like reactions in the tumor microenvironment.However,the efficacy of CDT is limited by low ROS generation efficiency,insufficient H₂O₂ concentration,and the type of exogenous Fenton reagent.To overcome these challenges,it will be particularly important to design functional nanocarriers for H₂O₂ replenishment,GSH depletion and promoting intracellular ROS production,and further promoting CDT efficacy.Therefore,in this thesis,two nanocarriers systems with synergistic targeting effects were successfully constructed based on MOC,which can be used not only to enhance the therapeutic effect of CDT,but also to combine CDT with CT to improve the anti-cancer activity of MOC in liver cancer.The main research results are as follows:（1）Construction and anticancer activity of mannose-modified ytterbium-based ferrocene nano-drug delivery system.The p H-responsive nanocarriers Fc-MOFs were synthesized by coordination self-assembly of 1,1’-ferrocenecarboxylic acid and ytterbium chloride under hydrothermal conditions,followed by loading of anticancer drug Doxorubicin（DOX）viaπ-πstacking and hydrogen bonding.Finally,the DOX@Fc-MOFs-Mann nanoparticles（NPs）were formed by charge interaction with the mannose derivative（Mann）.The testing via SEM,TEM,DLS and others show an average particle size of 275±15 nm with an irregular snowflake-like structure and a drug loading capacity of 9.3%.Extracellular experiments show a drug release rate of 70%after 48 hours in a p H=5.0 environment,and it effectively produces·OH in the presence of H₂O₂.The cell experiments showed that the DOX@Fc-MOFs-Mann NPs can actively target hepatocellular carcinoma cells（Hep G2）to achieve targeted delivery of anti-cancer drugs and to stimulate the release of drugs in the weakly acidic intracellular environment;ferrocene wae involved in the Fenton reaction to catalyze the conversion of intracellular H₂O₂ to highly toxic·OH;cytotoxicity analysis showed that the DOX@Fc-MOFs-Mann NPs have good biocompatibility and the survival rate of Hep G2 cells was only 20%after 48 h incubation,which effectively improved the efficacy of CDT and realized the combined treatment of CDT and CT.（2）Construction and anticancer activity of HA-modified p H/GSH dual-responsive copper-based triazole nanocarrier systems.The Cu-MOF was synthesized as a nucleus by coordination between the catalase（CAT）inhibitor 3-amino-1,2,4-triazole（3-AT）and Cu²⁺under hydrothermal conditions,followed by the growth of organic shells（SMON）on its surface using bis[3-（triethoxymethylsilyl）propyl]tetrasulphide and finally loading DOX and the targeting ligand hyaluronic acid（HA）by charge interaction/hydrogen bonding to obtain functionalized nano-agent Cu-MOF@SMON/DOX-HA.The SEM,TEM,DLS,and ultraviolet-visible（Uv-vis）experiments revealed that the average particle size of the Cu-MOF@SMON/DOX-HA NPs was approximately 300±15 nm and had a regular rod-like structure,with a DOX loading rate of 27.5%.The results of the extracellular experiments showed that the Cu-MOF@SMON/DOX-HA NPs had good p H/GSH responsiveness and was able to release 80%of the drug after 48 h in the presence of GSH with p H=5.0.It also displayed strong GSH consumption ability and·OH generation capacity.The results of cell experiments indicated that Cu-MOF@SMON/DOX-HA was able to effectively target Hep G2 cells,degrade and release DOX and 3-AT within the tumor microenvironment（TME）.SMON and Cu²⁺were able to consume a large amount of intracellular GSH and activate Fenton-like reactions,producing highly toxic·OH.The3-AT could effectively inhibited CAT activity and enhanced the efficiency of the Fenton-like reaction,resulting in the disruption of redox balance in cancer cells and successfully inducing cell ferroptosis.Finally,cytotoxicity analysis showed that the Cu-MOF@SMON/DOX-HA had good biocompatibility and only 8%survival rate after 48h incubation of Hep G2 cells,which provided an efficient way to improve the efficacy of CDT and achieve combination therapy.In summary,this paper constructs two tumor microenvironment-responsive nano-drug delivery systems based on nano-MOC for improving the efficacy of CDT,and successfully realizes the combination of CDT and CT for improving the anti-cancer activity of MOC for liver cancer.This nano-drug delivery system provides new strategy for the construction of functional MOC for dual-modality anti-cancer combination studies.