The Experimental Study Of The Synthesis And Effect Of A Novel Nano-Drug System Fe₃O₄@ZrMOF-Cys@CDDP-VPA@PDA On Hepatoma Cells

Background:Primary liver cancer has become one of the common malignant tumors in our country.The World Health Organization recently released the 2 0 2 0 global tumor burden data.In 2 0 2 0,the number of new liver cancer cases and deaths in China will account for 45%and 47%of the global new cases and deaths,respectively,which seriously threatens the lives and health of Chinese residents[1].Because liver cancer is not sensitive to radiotherapy and chemotherapy.Therefore,the current clinical treatment methods mainly include surgical resection,liver transplantation,and interventional therapy.Surgical resection and liver transplantation are still the preferred options for early treatment of liver cancer.However,due to the insidious onset of liver cancer,most patients are in the middle and late stages when diagnosed,thus losing the opportunity of resection and liver transplantation[2,3].According to statistics,only 15%-3 0%of newly diagnosed primary liver cancer patients can receive surgical treatment,and the postoperative recurrence rate is still as high as 36%-66%[4].The main problem of systemic chemotherapy is that chemotherapy drugs can not only kill tumor cells,but also damage normal human cells to varying degrees,and can cause a series of serious toxic and side effects.[5].These irreversible damages to body functions not only seriously affect the effectiveness of tumor treatment,but also greatly reduce the quality of life of patients.Therefore,improving the utilization rate of chemotherapeutic drugs and reducing the toxic and side effects on normal tissues has always been an urgent problem to be solved in tumor treatment research.[6].Metal-organic framework(MOF)material is composed of metal ions and organic ligands.As an organic-inorganic hybrid material,it combines the rigidity of inorganic materials-easy to control the structure and the flexibility of organic materials-degradable,Features of better biocompatibility.Because of its adjustable size,high drug loading,high porosity,and large specific surface area,it is widely used in tumor treatment.At the same time,MOF itself has the advantages of low toxicity and degradability,and has gradually become one of the preferred materials for tumor therapy drug carriers.Objective:In this project,ZrMOF is used as a nano-drug carrier material,Fe3O4 is loaded on the porous structure as a tracer,and the anti-tumor chemotherapeutic drug cis-platinum(CDDP)is loaded at the same time.Toxic and side effects of materials[7].Fitted into a new nano-drug system of Fe3O4@Zr-MOF-Cys@CDDP-VPA@PDA;the nano-drug system was verified by in vitro experiments to have dual imaging capabilities of CT/MRI,realizing the monitoring of drug treatment response by the controlled release system Purpose.The results of this study will provide a theoretical basis for the precise diagnosis and treatment of liver cancer.Methods:1.One-pot synthesis of ZrMOF metal drug-loaded frameworks was performed using the hot-melt reactor method;in order to increase the subsequent drug-loading capacity,1-cysteine hydrochloride(Cys)was added during the reaction[8];and a vacuum pump was used.The method of adding paramagnetic nanoparticles Fe3O4 on the basis of ZrMOF gave Fe3O4＠ZrMOF-Cys nanoparticles.At the same time,we added cisplatin drug(CDDP)and sodium valproate(VPA)[9,10],and finally coated with dopamine(PDA)to increase the biocompatibility of the nanodrug system and reduce the toxic and side effects of CDDP.Finally,the complete Fe3O4@ZrMOF-Cys@CDDP-VPA@PDA nano-drug system was obtained,and its physicochemical characterization was performed,and its CT/MRI imaging performance,drug release and material stability were tested.2.Different concentrations of Fe3O4@ZrMOF-Cys were co-cultured with HepG2 cells,and the cytotoxicity was detected by MTT method after 24 hours.To evaluate the in vitro biosafety of Fe3O4@ZrMOF-Cy s.HepG2 cells were incubated with different concentrations of Fe3O4@ZrMOF-Cys@CDDP-VPA@PDA for 24 hours,and the cell viability was detected by MTT method to evaluate the antitumor effect of Fe3 O4@ZrMOF-Cys@CDDP-VPA@PDA.Results:1.ZrMOF was successfully prepared,with an average particle size of about 150 nm,hexahedral structure,uneven distribution and smooth surface.ZrMOF-Cys nanoparticles were successfully synthesized,and EDS spectra showed N and S elements,that is,Cys existed inside the ZrMOF framework.XRD showed that it had a good crystal structure.The scanning results of transmission electron microscopy confirmed that the Fe3O4 paramagnetic particles were successfully combined and supported on the surface of the metal frame.The particle size was about 18 5nm,the surface was rough,and the size was relatively uniform.2.The chemical composition and structure of the as-prepared ZrMOF@CDDP were evaluated by FT-IR method.We recorded the FT-IR spectral peaks of ZrMOF,CDDP and ZrMOF@CDDP,the characteristic absorption peak of C-O at 1060 cm-1 is the stretching vibration peak of O-H,and the wavenumbers at 2959 cm-1 and 2870 cm-1 are C-H The characteristic absorption peaks at 3410 cm-1 and 680 cm-1 of the stretching vibration are the plane bending vibration peaks of O-H,indicating the successful synthesis of ZrMOF nanoparticles.Compared with the spectrum of CDDP,the spectrum of ZrMOF@CDDP has additional adsorption bands at 1506 cm-1 and 1592 cm-1,belonging to aromatic CC stretching vibrations,indicating the successful connection of CDDP to ZrMOF.3.The CDDP cisplatin drug was tested for drug loading and drug release by high performance liquid chromatography.The drug loading rate and encapsulation rate were 22.7%and 49.5%,respectively.The release capacity of CDDP under the condition of pH=5.4 was higher than that under the condition of pH=7.4.At 50 hours,the release rate of the former was close to 47%,while the release rate of the latter was less than 8%.Fe3O4@ZrMOF has CT/MRI dual-modality imaging function,and the relaxation efficiency r2 value is 83.86mM/s.4.Fe3O4@ZrMOF has good cytocompatibility and does not cause obvious cytostatic effect in the concentration range of 12.5-100 μg/mL.Conclusion:In this project,controllable ZrMOF modified with 1-cysteine hydrochloride is used as a nano-drug carrier material,Fe3O4 is loaded in the mesopores as a tracer,and an anti-tumor chemotherapeutic drug cisplatin is loaded at the same time.(cis-platinum,CDDP)and sodium valproate(Sodium Valproate,VP A),and coated with dopamine PDA,a novel nano-drug system of Fe3O4@Zr-MOF-Cys@CDDP-VPA@PDA was synthesized.In vitro experiments showed that Fe3O4＠ZrMOF-Cys@CDDP-VPA has good physicochemical properties,good drug-carrying capacity,CT/MRI dual-modality imaging and anti-tumor therapeutic effects,as well as good biological safety.This study provides a new research idea for the development of a new nano-drug system and its application in CT/MRI dual-modality image-guided chemotherapy.