A Biomimetic Iron-based Metal-organic Framworks Loading With Glucose Oxidase For Combination Tumor Therapy

In order to maximize the therapeutic efficacy,it is necessary to improve the tumor targeting capacity in starvation therapy,gas therapy or chemodynamic therapy.Appropriate nanocarriers can accurately deliver effector molecules or drugs that mediate starvation therapy,gas therapy,and photodynamic therapy to the tumor site,reducing the side effects caused by off-target and improving the therapeutic effects.Metal-organic frameworks(MOF)are nano-sized matierals with huge surface area,internal porous and convenient size adjustment,suitable as drug carriers for tumor treatment.Unlike other nano-carriers such as porous silicon,the organic ligands in MOF can be selected independently,resulting in rich properties and functions of MOF.This project combined starvation therapy,gas therapy and chemodynamic therapy for cancer therapy.Iron porphyrin(Fe-TCPP),which can catalyze arginine to produce nitric oxide(NO),was selected as the ligand to coordinate with zirconium ion to form iron-based MOF(Fe-MOF).Fe-MOF was used as a carrier to load glucose oxidase(GOx)and then wrapped with cancer cell membrane to prepare CM@Fe-MOF@GOx.Using the homologous targeting ability of cancer cell membranes,CM@Fe-MOF@GOx was efficiently deliver to tumor cells.CM@Fe-MOF@GOx could effectively decompose arginine to produce NO to realize gas therapy.Meanwhile,when CM@Fe-MOF@GOx was used to mediate tumor starvation treatment,H₂O₂ produced by GOx-mediated glucose decomposition could react with iron ions in Fe-MOF to produce reactive oxygen species(ROS),which was used for chemodynamic treatment of tumors.Thus,CM@Fe-MOF@GOx achieved a multi-modal tumor combination therapy.The main research contents and results are as follows:1)Fe-TCPP was first synthesized,and then Fe-MOF was successfully prepared by solvothermal method.Fe-MOF exhibited a regular elliptical sphere with a hydrodynamic diameter of about 112 nm.Fourier transform infrared spectroscopy(FTIR)results showed that Fe-MOF has characteristic peaks consistent with Fe-TCPP.X-ray photoelectron spectroscopy(XPS)showed that the iron ions in Fe-MOF existed in divalent and trivalent forms,which can participate in the Fenton reaction.2)CM@Fe-MOF@GOx was constructed by Fe-MOF@GOx was prepared by adsorbing GOx in Fe-MOF and then wrapping H22 cell membrane by liposome extruder.CM@Fe-MOF@GOx has a uniform size with a hydrodynamic diameter of about 120 nm.It could catalyze to produce of NO and ROS,and could maintain the stability of GOx.It could be used for tumor starvation therapy,gas therapy and chemodynamic therapy.3)CM@Fe-MOF@GOx could effectively be internalized into H22 cells and produce NO and ROS to kill tumor cells.After CM@Fe-MOF@GOx entered cells,it could greatly reduce the contents of intracellular ATP to block the energy supply of tumor cells.Cytotoxicic experiments showed that CM@Fe-MOF@GOx could effectively kill H22 cells.4)In vivo experiments showed that CM@Fe-MOF@GOx could effectively target to tumor tissues of H22 tumor-bearing mice.CM@Fe-MOF@GOx could efficiently inhibit the tumor growth and extend the survival time of H22 tumor-bearing mice.Biological safety experiments showed that CM@Fe-MOF@GOx had very low side effect and negligible damage to normal tissues.In summary,CM@Fe-MOF@GOx could mediate starvation therapy,gas therapy and chemodynamic therapy for tumor therapy,showing a multi-modal combination therapy effect.CM@Fe-MOF@GOx might exhibit broad application prospects in tumor therapy.