Study On The Construction And Performance Of Multifunctional Drug Carrier Based On MOFs

Early diagnosis and simultaneous treatment of cancer are currently effective methods to improve the efficiency of cancer treatment.The design of multifunctional drug carriers integrating diagnostic and therapeutic functions has become a research hotspot.The metal-organic framework is a coordination compound with a periodic structure assembled by organic ligands and metal ions through coordination bonds.MOFs materials have potential applications in fluorescence,catalysis,gas adsorption and separation,proton conductors,and drug transport.In the past ten years,due to the advantages of large drug loading,easy modification,and low cytotoxicity,MOF has been widely studied for its application value in drug transportation.However,simple MOF is difficult to achieve precise drug release and it is difficult to meet the needs of cancer treatment and diagnosis.In order to make full use of the advantages of MOF,a variety of composite materials based on MOF have been designed.By combining MOFs materials with other materials,an ideal multifunctional drug carrier with integrated diagnosis and treatment can be achieved.The composite material was characterized by XRD,IR,SEM,TEM,etc.,and its structure was proved.The imaging performance and drug release performance of the composite material under different p H conditions was studied using methotrexate and doxorubicin as drug models.The detailed work of this article is carried out from the following aspects:In Chapter 1,eight types of cancer treatments were introduced in detail,including chemotherapy,gene therapy,immunotherapy,photodynamic therapy,photothermotherapy,chemotherapy,magnetic thermotherapy,and chemokinetic therapy.The advantages and disadvantages of these methods were discussed,and effect of these methods were elucilated..After that,the nanomaterials used in biomedicine were introduced,and the functions and applications of these materials were discussed.Finally,the application of the metal-organic framework in biomedicine was introduced,and the stability,toxicity,and possibility of being used as a drug carrier and cancer diagnosis were described.In Chapter 2,a composite of stable fluorescent materials based on MOFs was synthesized.First,Zr-MOF was synthesized by hydrothermal method,then the fluorescent group"acetaldehyde-modified cystine（AMC）"and MOFs were hybridized to synthesize Zr-MOF/AMC composites.All materials were characterized by XRD,IR,SEM,TEM,and DLS,and their structures were proved.Through fluorescence spectrum detection,it was proved with strong and stable fluorescence performance.The fluorescence detection of GSH solutions with different concentrations proved the application in detection GSH with the detection limit of 4.624μmol L^-1.Methotrexate（MTX）was used as a drug model,and the controlled release ability of Zr-MOF/AMC to MTX was studied.It was proved that the75%MTX can be released in the conditions similar to the tumor microenvironment,achieving the requirements of p H/GSH dual-targeted controlled release.The drug carrier can make fluorescent recognition of abnormal GSH in the tumor microenvironment,and can realize accurate drug release for treatment.As a result,the function of"diagnosis and treatment integration".can be obtained.In Chapter 3,a“dual-key and-Lock”drug carrier was designed to respond to tumor microenvironment.A core-shell Fe-MOFs@ZIF-8 was synthesized,with ZIF-8 as shell（the first lock）to encapsulate catalase,Fe-MOFs as core（the second lock）to encapsulate anticancer drug doxorubicin（DOX）.Fe-MOs@ZIF-8 takes advantage of tumor microenvironment includes high concentration of H₂O₂,weak acidic environment and hypoxia to achieve cancer therapy.With the p H response,the ZIF-8 and the Fe-MOFs will be degraded in turn to release catalase and DOX,just like"p H stimulation"as a key to open two locks in turn.After the first lock is opened（degradation of ZIF-8）,catalase is released and reacts with rich H₂O₂in tumor to produce O₂to regulate hypoxia,thereby improving the anti-cancer efficiency of released DOX after the second lock is opened（degradation of Fe-MOFs）.Furthmore,after the degradation of Fe-MOFs,Fe³⁺was released and reduced to Fe²⁺by H₂O₂,which will be as Fenton catalyst to react with H₂O₂to produce hydroxyl radicals to kill more cancer cells.The Fe-MOFs@ZIF-8 exhibit good dispersion and stability and p H and H₂O₂-dual responsive drug release profile.The different cytotoxicity to L-02 cells and He La cells of Fe-MOFs@ZIF-8 shows Fe-MOFs@ZIF-8 is only harmful to cancer cells and not harmful to normal cells.The reason is that the released iron ions interact with rich H₂O₂in cancer cells to generate hydroxyl radicals（?OH）,which is proved by the color change by the solution of 3,3’,5,5’-tetramethylbenzidine turns blue.After loading the drug and catalase.Fe-MOFs@ZIF-8 shows more cytotoxicity to He La cells,indicating excellent hypoxia cancer therapy effect.Therefore,construction of“Dual-Key-and-Lock”drug carriers respond to cancer cells are a promising strategy for cancer treatment.In Chapter 4,different proportions of heterometallic ligands MOFs were synthesized by hydrothermal method,and 5 kinds of Fe-Tm heterometallic MOFs were synthesized by changing the proportion of ligands（pyrimellitic acid and 2-methylimidazole）.The structures were proved by XRD,IR,SEM,TEM,and DLS.By studying the fluorescence performance and photothermal effect of MOFs with different proportions of heterometallic ligands,MOFs with the ratio of 1:1 was found to be with the best morphology and the strongest fluorescence performance.The photothermal effect was proved excellent because the temperature reached 47℃in 10 minutes,above the temperature killing tumor cells.A biological application test was performed on 1:1 MOFs,and it was found to be with good biocompatibility and good p H response to drug release.The released drug reached 82%at p H5.8.In vivo anticancer experiment were performed.It was found that the tumors of the mice with the injection of drug-loaded materials and near-infrared light irradiation almost disappeared in 10 days,proving the potential development of the material in synergistic therapy.