Construction Of Dihydroartemisinin Metal-Organic Framework Composite And Its Application In The Study Of Tumor Ferroptosis

Chemotherapy is a classic approach to treating cancer,but chemotherapy drugs can induce drug resistance in tumor cells,increasing the difficulty of tumor treatment.Dihydroartemisinin（DHA）is a Ferroptosis inducer,is widely used in cancer treatment,mainly by reacting with excess iron ions in cancer cells to produce Reactive Oxygen Species（ROS）,which exerts therapeutic effects.However,DHA is poorly water-soluble and difficult to be enriched to tumor tissue sites;Glutathione（GSH）-based antioxidants in the Tumor Microenvironment（TME）inhibit the effect of DHA and the occurrence of Ferroptosis.Ferroptosis is a form of cell death distinct from apoptosis that can bypass the drug resistance of tumor cells to exert efficient tumor-killing effects.Therefore,breaking through the limitations of chemotherapeutic drugs and enhancing Ferroptosis pathway are the keys to improving the effects of chemotherapeutic drugs.On this basis,Metal-Organic Frameworks（MOF）with GSH-responsive function as DHA carriers can not only deliver drugs to tumor cells,but also deplete GSH to disrupt the antioxidant defense system of TEM and enhance the effect of DHA to induce Ferroptosis.Based on the above background,this study constructed a MOF-based drug delivery platform Cu-MOF-DHA-F-127（CMD）with the objectives of disrupting redox homeostasis,enhancing the anti-tumor effect of DHA,and activating Ferroptosis pathway in tumor therapy.Details of the work are as follows:1.Synthesis of CMD and characterization of its physicochemical propertiesA DHA-loaded,GSH-responsive MOF nanoplatform CMD was synthesized by liquid-phase method and characterized by transmission electron microscopy,Fourier transform infrared absorption spectroscopy,powder X-ray diffractometer,and UV-Vis spectrophotometer.The CMD size was 100～200 nm and its drug loading efficiency was about 22%.CMD undergo structural disintegration in response to GSH to release DHA,while consuming GSH in a time-and concentration-dependent manner.2.To investigate the effect of CMD in killing tumors at the cellular levelThe endocytosis assay showed that CMD could be taken up by cancer cells.The results of the 3-（4,5-dimethylthiazol-2）-2,5-diphenyltetrazolium bromide salt（MTT）assay illustrate the selective killing effect of CMD on human breast cancer cells MDA-MB-231cells,while reducing the toxic effects of DHA on normal cells L929 cells.Similar to the results of the experiments at the test tube level,CMD was also able to deplete GSH in cells and exhibited time-dependent and concentration-dependent properties.Flow cytometry and confocal fluorescence microscopy detected large amounts of ROS generated by CMD in cancer cells to induce apoptosis.The activation of the cellular iron death pathway by CMD was demonstrated using the iron ion chelator desferrioxamine mesylate（DFO）and the fluorescent probe C11-BODIPY^581/591 that detects lipid peroxidation.3.To investigate the effect of CMD in killing tumors at the in vivo levelThe efficacy of CMD in nude mice was evaluated by recording the weight change,tumor size change and final weight of the tumor.The morphological changes of tumor tissues and major organs were also observed by H&E and TUNEL staining to evaluate the antitumor activity and drug safety.The results showed that CMD had a good inhibitory effect on tumor tissues with good biosafety and caused no significant damage to the major organs of nude mice.The above experimental results provide an effective strategy for the practical application of DHA in tumor therapy.The above experimental results show that CMD with GSH responsive function can not only deliver DHA to tumor tissues,but also deplete GSH and enhance DHA action to induce Ferroptosis.The design idea of CMD provides an effective strategy for the practical application of DHA in tumor therapy.