Abstract Compared with traditional materials， metal-organic framework materials （MOFs） have the characteristics of drug release controllability， degradability， designability and adjustability of composition and structure， excellent load capacity， and designability and adjustability of channel shape and size， and have shown a wide range of application value in the field of biomedicine. In this paper， based on the structural characteristics of MOFs， the synthetic design of MOF materials was expounded， and the research achievements of MOF materials in biomedicine in recent years were reviewed.
　　Key words Metal-organic framework material; Synthesis; Biomedicine; Application
　　 Compared with traditional materials， new porous materials MOFs have unlimited potential in the field of biomedicine[1]. Metal-organic frameworks （MOFs） are crystalline substances produced by the combination of metal ions and organic ligands. They are porous and can facilitate the loading of some biological molecules （biogas， anti-tumor drugs）. When MOFs enter the in vivo microenvironment for drug delivery and release， functional Lewis base sites and acid sites in organic ligands preferentially correspond to binding sites. MOF materials also have open metal complex sites， which can ensure the controlled release performance of drug carriers， so they can play a huge role in the fields of molecular detection， disease diagnosis and treatment， drug delivery， biological imaging and so on.
　　Features of MOF materials
　　Compared with traditional inorganic porous materials， metal organic frameworks have the following characteristics：
　　Preparation methods of MOF materials
　　Most of the MOFs can be prepared by the room temperature volatilization method[2]， hydrothermal method[3-6]， diffusion method[7-8]， microwave method[9-10]， template method[11-12]， and stirring synthesis method[13]. Among them， the reaction temperature of the hydrothermal method is lower （less than 200 ℃）， and the synthesis method is mild and controllable.
　　Frame structures of MOF materials
　　The metal center and the organic ligand are assembled through reversible coordination bonds. Compared with the general supramolecular materials obtained through hydrophobic interaction， π-π interaction and ammonia bonding， MOFs have better thermal and chemical stability.
　　Characterization of MOF materials
　　The means of characterizing the structure and performance of MOFs mainly include the following aspects： ① determine the crystal structure by single crystal X-ray diffraction， ② characterize the crystallinity and phase purity of MOFs by powder X-ray diffraction， ③ determine the pore size distribution and specific surface area of MOFs by gas adsorption tests， ④ observe the surface morphology and size distribution of MOFs by electron microscopy， and ⑤ determine their structural composition by ultraviolet， infrared， solid-state nuclear magnetic and other characterization methods[14 ]. 　　Types of synthesis design of MOF materials
　　Classification by metal ion and ligand types
　　IR MOF series
　　MOF-5 （IRMOF-1） is the most typical MOF material. It is prepared from Zn2+ and terephthalic acid by a relatively mature synthesis method and has a stable structure. It has been widely used in gas storage and adsorption， photocatalysis， etc. As early as 1999， the Yaghi research team[15] successfully synthesized the MOF-5 material with a cubic three-dimensional structure for the first time. Afterwards， other MOF materials such as new MOF-180， MOF-200， MOF-525 and MOF-555 synthesized by changing the ligand length[16-17] have also been reported in successive.
　　MIL MOF series
　　The MIL series MOFs are prepared from transition metals such as Cr， Fe， V or lanthanide metals and dicarboxylic acid ligands such as terephthalic acid. Ferey[18] used Cr3+ and 1，3，5-benzenetricarboxylic acid to synthesize powdered MIL-100 MOF with high specific surface area and multi-level pore system under hydrothermal conditions. Subsequently， the research team reported the synthesis of MIL-101 porous MOF with larger pore size and specific surface area than the former[19].
　　ZIF MOF series
　　The organic ligands of the ZIF series are nitrogen-containing imidazoles or imidazole derivatives. The ZIF series is named because they have a three-dimensional network structure similar to zeolite， that is， the metal ions in the ZIF series materials replace Si and Al of the zeolite， and the organic ligands replace oxygen. They have the characteristics of the zeolite material including structural stability， rich spatial structure and chemical stability， and have very good application prospects. As early as 2006， the Yaghi research team[20] reported the synthesis of a series of materials from ZIF-1to ZIF-12.
　　UIO MOF series
　　This series of MOFs are two-dimensional porous materials constructed with Zr4+ and dicarboxylic acid ligands. They mainly contain UiO-66， UiO-67 and UiO-68. The series of MOFs have good high temperature stability and are suitable for photocatalysis， adsorption， sensor and other fields， having very good application prospects.
　　Classification by framework structure
　　1D MOF materials
　　The Lius research group[21] developed a phase transfer method to construct PEGylated one-dimensional MOFs in one step. These one-dimensional MOFs not only have good dispersion and long blood circulation time， but also can realize charge reversal in the slightly acid environment of tumors， which directly improves the retention and enrichment of the drug carriers in tumors. Boxuan Yu et al.[22] modified the inner surface of the polycarbonate track etched membrane （PCTM） columnar channel for the first time using PDA chemistry to obtain a ZIF-8 hollow superstructure with a good one-dimensional channel embedded in the membrane matrix， which was first used as an integrated chromatography microcolumn array effectively capturing uranium from aqueous solutions. 　　2D MOF materials
　　Due to its superior performance， the synthesis methods of 2D MOFs are endless， and there are many methods for preparing 2D MOFs. Beauvais et al.[23] prepared new 2D MOFs constructed from tetra（4-carboxyphenyl） porphyrin ligands and Cd（II） sites using metal sites of hetero-bimetallic framework technology. Based on the reported Zn-TCPPMOFs[25]， Zhang et al.[24] obtained 2D Zn-TCPP nanosheets by the surfactant-assisted method for the first time. With the in-depth study of MOFs， relevant researchers have gradually prepared 2D MOFs or MOFs thin film[26] materials and applied them to SPR biosensors. Guo et al.[27] reported that MWCNTs-BMIMPF6 composite material was used to immobilize nucleic acid aptamer chains and then to detect kanamycin. The minimum detection line was 0.507 ng/ml. Ding et al.[28] constructed a PCNR/GR-Fe3O4-AuNPs electrochemical nucleic acid aptamer sensor， which has high sensitivity for the detection of streptomycin.
　　3D MOF materials
　　Three-dimensional porous nanomaterials refer to a class of materials that form a network structure through pores that are closed or interpenetrating with each other. Deng[29] synthesized Fe-MIL-88NH2 and used it to develop an electrochemical biosensor for C-reactive protein and single nucleotide polymorphism （SNP） detection. Chen[30] synthesized and characterized the 3D MOF material of {[Cu（Cdcbp）（bipy）]·4H2O}n（1）， and ligand coupling， positively charged pyridine center and Cu（II） cation make it capable of effectively hybridizing with thymine-rich DNA， which helps to explain the occurrence of related diseases， such as neurodegenerative diseases of Parkinsons disease and Alzheimers disease.
　　Classification by function
　　The functionalization of MOFs mainly includes pre-synthesis functionalization and post-synthesis functionalization. The functionalization of MOFs before synthesis is usually to introduce functional groups on organic ligands， and then select a suitable synthetic method to construct MOF materials. This method may require higher synthesis conditions， and the introduction of functional groups is likely to affect the framework， so it is not suitable for modification of all MOFs. The functionalization of MOFs after synthesis is currently a relatively common method， which can modify MOFs by in-situ organic reactions， and the reaction sites can be on organic ligands or metal centers. However， this method has relatively high requirements on the stability， channel properties and surface properties of MOFs. Liu et al.[31] chose an aminated MOF facilitating post-modification as a drug carrier and applied it to cell imaging and chemo-photodynamic therapy. The experiment showed that the synergistic treatment method has a higher therapeutic effect than single treatment. 　　Research and Application of MOF Materials in Biomedicine
　　Although the research of MOFs in the field of biomedicine has attracted extensive attention from researchers， but so far the results published have not been much.
　　Application of MOFs in drug carrier
　　Nano drug carriers constructed based on MOFs have been continuously developed in basic research fields such as tumor chemotherapy， photodynamic therapy， photothermal therapy， immunotherapy and combination therapy. The team of Zhang and Zhong[32] designed and constructed a nano-platform for tumor therapy based on MOFs. In this design， MOFs were used to carry monocarboxylic acid transporter 1 （MCT1） inhibitors， which greatly improved the efficacy of photodynamic therapy. Willners research group[33] used MOF nanoparticles to load the anticancer drug DOX， and modified an ATP-responsive polyacrylamide/DNA hydrogel on the surface of MOFs. Ke[34] prepared a new type of magnetic core-shell microsphere Fe3O4@MIL-100 （Fe）， which not only has good targeted drug loading characteristics， but also solves the problem of carrier biocompatibility and toxicity. The above material can reduce the number of administration of nimesulide in clinical， providing a reference for the ideal candidate materials of targeted drug loading.
　　Application of MOF materials in DNA detection
　　Based on AuPt-MB as a new redox nano-signal probe combined with N-GNRs-Fe-MOFs@AuNPs nano-composite modified electrode as a sensor component， Tang[35] designed a sandwich immune biosensor for specific detection of galectin-3 （Gal-3）. The biosensor has achieved satisfactory detection results in the analysis of human blood samples. Chens research group first implemented the application of MOFs in the detection of HIV DNA fragments[36]. Using dithiooxamide （H4dtoa） and copper sulfate as raw materials， a two-dimensional metal organic framework Cu （H4dtoa） was obtained. The framework has the characteristics of large specific surface area and strong conjugation effect. It can be combined with fluorescently labeled DNA by π-π stacking and hydrogen bonding to form a composite system， and can quench the fluorescence of the labeled DNA by the photo-induced electron transfer （PET） mechanism. When the HIV DNA fragment or thrombin as the target appears， the labeled DNA is combined with the target and detached from the composite system， and the fluorescence is restored. By examining the change in the fluorescence intensity of the system， the target can be detected. 　　Application of MOF materials in medical imaging
　　With the development of medical technology， although people have long recognized the importance of early detection for the effective treatment of cancer， the current limited recognition and diagnostic techniques for tumors often make patients diagnosed in the late stage of cancer， and miss the best treatment time. Conventional diagnostic agents， such as gadolinium chelates on magnetic resonance imaging， have short action times and high toxic side effects， which limits their clinical use. More and more researchers are trying to apply MOFs on MRI contrast agents. Based on the fact that MOFs constructed with amphoteric carboxylic acid ligands have the advantage of being stable to water， Qin[37] constructed two water-stabilized MOFs using H3CmdcpBr as a ligand， and Mn2+ and Gd3+ ions with more unpaired electrons and larger magnetic moment， magnetic susceptibility and longer electron spin relaxation time， respectively， and obtained an MRI contrast agent with high longitudinal relaxation efficiency and good imaging effect.
　　Prospects
　　Although bio-functionalized nanomaterials based on MOFs have made some important breakthroughs in the field of biomedicine， it still takes a long time to apply them in clinical treatment. First of all， it is necessary to optimize the design and synthesis of materials and develop nano-pharmaceutical carriers with good biocompatibility and no toxicity or low toxicity. These nano-drug carriers need to be able to perform long circulation in the blood and can be effectively metabolized and excreted. Secondly， the stability of MOFs in organisms and their biodegradable mechanism need further study. Biological tissues are complex in structure and dynamics. Building dynamic response biomaterials based on MOFs which respond to specific physiological stimuli by targeting and regularly releasing bioactive molecules has important research significance and application prospects.
　　Agricultural Biotechnology2020
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