Preparation Of Iron-based Nanoscale Coordination Polymers With Good Biocompatibility And Their Applications For Ferroptosis

In recent years,cancer has become one of the major diseases that threaten human health.Traditional cancer treatment methods have the disadvantages of large side effects and easy to produce drug resistance.Therefore,it is urgent to develop cancer treatments around new ways of cell's death.Ferroptosis is a form of regulated cell death which different from apoptosis and autophagy.It was caused by an abnormal increasing of intracellular lipid reactive oxygen species and an imbalance of redox homeostasis derived from iron metabolism.Different cancer treatments had been designed based on the characteristics of tumor microenvironment and the mechanism of ferroptosis.It is one of the strategy to induce Fenton reaction in cells,which is to induce high levels of cancer cells by introducing iron to cells.Hydrogen peroxide can be converted to highly toxic·OH which will kill cancer cells by attacking the cell membranes and the nucleus.Minwhile,iron-based coordination polymer materials have great application potential in ferroptosis with its excellent degradability and biocompatibility.Based on the above background,it is meaningful to construct a nano-treatment platform of ferroptosis to cancer treatment.Therefore,we synthesized iron-based nanoscale coordination polymers with good biocompatibility,and then applied them to tumor therapy.The specific work contents are as follows:1.Preparation of nanoscale coordination polymers based on sulfosalicylic acid/Fe³⁺and their application in ferroptosisSulfosalicylic acid?SSA?,a derivative of salicylic acid,was used as organic ligand and Fe³⁺ion was used as metal center for the synthesis of PFNCs by the solvothermal method.The surface of the PFNCs was further modified by NH₂-PEG.As-prepared PFNCs have good stability in the neutral condition but can be degraded in acidic tumor microenvironment.The results show that the ligand SSA dissociated from PFNC with the average size of¹40 nm can lead to the decrease of GSH and the accumulation of H₂O₂ in cancer cells,which thus elevates cellular ROS via the Fenton reaction.In addition,SSA can significantly enhance the cytotoxicity of iron ions.The typical features,including iron-dependent property,morphological changes of dead cells and the lipid peroxidation had been observed in PFNCs-treated MCF-7 cells.It demonstrated that the ferroptosis is one of the causes for PFNCs-induced cell death.Due to the decomposition of hydrogen peroxide by catalase in normal cells,the toxic of PFNC is lower to normal cells than cancer cells.In vivo experiments show that the tumors from PFNCs-treated group?0.15 g?are obviously smaller than these from PBS-treated group?0.90 g?after 16 days treatment,clearly demonstrating that the intravenous administration of PFNCs can significantly inhibit the tumor growth.The results of histological analysis?H&E staining?show that major organs of mice have not been damaged by PFNCs.During the experiment,we also found that PFNC does not have the ability to load small molecules of drugs,which will greatly limit the futher application in the combination of ferroptosis and other therapies.2.Preparation of cisplatin-loaded MIL-101?Fe?nanoparticles and their application in ferroptosisConsidering the fact that PFNC can not load small-molecule drugs,in this section we have synthesized porous MIL-101 nanoparticles by solvothermal methods.TEM observation showed that the size of MIL-101 is about 300 nm and has good dispersibility and can adsorbe cisplatin.We also performed X-ray diffraction?XRD?characterization of resulting MIL-101 which was consistent with the result reported in the literature,which proves that we have synthesized MIL-101.Experimental results show that MIL-101 has good load capacity of cisplatin.In vitro experiments showed that the cytotoxicity of MIL-101 loaded with cisplatin was significantly higher than that of cisplatin alone.And it was significantly reduced after the addition of DFO which showed that iron plays a key role in the cytotoxicity of the nanoparticals.