Iron-Based Metal-Organic Framework Nano-Drug Induces Ferroptosis Mechanism And Its Application In Tumor Therapy

Ferroptosis is a form of regulatory cell death found in recent years which depends on the concentration of intracellular iron ions and reactive oxygen species.It is very different from other cell death forms such as apoptosis,cell necrosis,and autophagy in cell morphology and mechanism.The mechanism of ferroptosis is regulated by a series of complex gene expression and signal transduction.which has not yet been studied clearly.Up to now,many iron nanomaterials,such as superparamagnetic iron oxide nanoparticles,amorphous iron nanoparticles and iron-based metal-organic framework nanoparticles,have been widely studied in anti-cancer therapy area because of excessively accumulated iron ions in cells which responsible for cell oxidative damage.However,their anti-tumor mechanisms have not been studied clearly.Therefore,study of the mechanism iron nanoparticles caused cell death is of great significance for the development of cancer therapeutic drugs.In this study we designed a liposome-modified iron-based metal organic framework nanodrug BSO@MOF-Lip to study the mechanism of cell death BSO@MOF-Lip caused and apply the nanodrug to tumor therapy.The main research contents include:Ⅰ.The synthesis of BSO@MOF-Lip,a metal-organic framework nanodrug,and its physicochemical properties and stability characterization.The results show that we have synthesized spindle-shaped nano metal-organic framework nanodrug carrier MOF with a diameter of 40-50 nm and a length of 100-160 nm.The morphology and size of BSO@MOF and BSO@MOF-Lip are basically unchanged after drug loading and liposome modification.The stability of BSO@MOF-Lip nanodrug was enhanced after modification.Under simulated physiological conditions,the particle size of BSO@MOF-Lip did not change significantly,which proves that the synthesized nano-drug could be applied to the research in cellular level.Ⅱ.The mechanism of cytotoxicity of BSO@MOF-Lip was explored.The results showed that its cytotoxicity effect on breast cancer cell line 4T1 was stronger than that of normal cell line NIH-3T3,and its cytotoxicity effect could be changed by iron death regulator.The iron death-related metabolites such as glutathione amount,lipid peroxidation degree of cell membrane,glutathione peroxidase activity and reactive oxygen species increased in 4T1 cells when treated with BSO@MOF-Lip.In accordance with the known mechanism of iron death,BSO@MOF-Lip can induce ferroptosis in cancer cells.Ⅲ.The design and synthesis of BSO&OXA@MOF-Lip-RGD,a complex nanodrug based on inducing ferroptosis of cancer cells and chemotherapeutics,was used to apply to cancer therapy.The results showed synergistic anti-tumor effect in cellular and animal levels.