γ-环糊精金属有机骨架材料提高难溶性药物二氟尼柳的溶出速率
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摘要
本研究的目的是合成生物相容性优良的新型多孔材料γ-环糊精金属有机骨架(γ-cyclodextrin metal-organicframework, CD-MOF),并探究其作为药物载体改善难溶性药物体外释放行为。通过γ-环糊精与钾离子的分子自组装效应堆积形成骨架结构,并调控晶体的生长速率,得到不同粒径的CD-MOF。以难溶性药物二氟尼柳(diflunisal,DIF)为模型药物,利用浸渍法将药物装载至CD-MOF的孔道。采用扫描电镜、粉末X-射线衍射、N_2吸附-解吸附、傅里叶红外光谱和热重分析等方法对不同尺寸多孔材料进行表征,并考察载体的细胞毒性和提高难溶性药物溶出速率的能力。实验结果表明,合成的CD-MOF呈孔道多样的立方体形貌、粒径均一、比表面积大和细胞毒性小。药物负载前后载体的形貌和晶型均未改变,难溶性药物二氟尼柳的溶解度和溶出速率显著提高。
The aim of this study is to prepare porous γ-cyclodextrin metal-organic framework(CD-MOF)with good biocompatibility to improve the in vitro release properties of water-insoluble drugs. Different sizes of CD-MOF were obtained by controlling the self-assembly of γ-cyclodextrin and potassium ion and the rate ofcrystal growth. The poorly water-soluble diflunisal(DIF) was selected as the model drug and loaded into theinterior of porous CD-MOF by the impregnation method. The DIF loaded CD-MOF(DIF-MOF) was characterizedby scanning electron microscopy(SEM), powder X-ray diffraction(PXRD), nitrogen adsorption and desorption,Fourier infrared spectrometer and thermogravimetric analysis. In addition, in vitro cytotoxicity and solubilizingcapability of CD-MOF were investigated. It revealed that the obtained CD-MOF was cubic-like with a narrow sizedistribution and high porosity. Negligible cytotoxicity was found after incubation with RAW264.7 cells. Comparedwith the pure CD-MOF carrier, the morphology and crystal form of DIF-MOF was not damaged during the drugloading process. Moreover, the solubility and release rate of water-insoluble DIF from the DIF-MOF were signifi-cantly increased.
The aim of this study is to prepare porous γ-cyclodextrin metal-organic framework(CD-MOF)with good biocompatibility to improve the in vitro release properties of water-insoluble drugs. Different sizes of CD-MOF were obtained by controlling the self-assembly of γ-cyclodextrin and potassium ion and the rate ofcrystal growth. The poorly water-soluble diflunisal(DIF) was selected as the model drug and loaded into theinterior of porous CD-MOF by the impregnation method. The DIF loaded CD-MOF(DIF-MOF) was characterizedby scanning electron microscopy(SEM), powder X-ray diffraction(PXRD), nitrogen adsorption and desorption,Fourier infrared spectrometer and thermogravimetric analysis. In addition, in vitro cytotoxicity and solubilizingcapability of CD-MOF were investigated. It revealed that the obtained CD-MOF was cubic-like with a narrow sizedistribution and high porosity. Negligible cytotoxicity was found after incubation with RAW264.7 cells. Comparedwith the pure CD-MOF carrier, the morphology and crystal form of DIF-MOF was not damaged during the drugloading process. Moreover, the solubility and release rate of water-insoluble DIF from the DIF-MOF were signifi-cantly increased.
引文
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[5]Ren H,Zhu GS.Porous organic frameworks:synthetic strategy and their applications[J].Acta Chim Sin(化学学报),2015,73:587-599.
[6]Wu MX,Yang YW.Metal-organic framework(MOF)-based drug/cargo delivery and cancer therapy[J].Adv Mater,2017.DOI:10.1002/adma.201606134.
[7]Forgan RS,Smaldone RA,Gassensmith JJ,et al.Nanoporous carbohydrate metal-organic frameworks[J].J Am Chem Soc,2012,134:406-417.
[8]Hartlieb KJ,Holcroft JM,Moghadam PZ,et al.CD-MOF:a versatile separation medium[J].J Am Chem Soc,2016,138:2292-2301.
[9]Eddaoudi M,Kim J,Rosi N,et al.Systematic design of pore size and functionality in isoreticular MOFs and their application in methane storage[J].Science,2002,295:469-472.
[10]Gassensmith JJ,Furukawa H,Smaldone RA,et al.Strong and reversible binding of carbon dioxide in a green metal-organic framework[J].J Am Chem Soc,2011,133:15312-15315.
[11]Li HY,Lv NN,Li X,et al.Composite CD-MOF nanocrystalscontaining microspheres for sustained drug delivery[J].Nanoscale,2017,9:7454-7463.
[12]Hartlieb KJ,Ferris DP,Holcroft JM,et al.Encapsulation of ibuprofen in CD-MOF and related bioavailability studies[J].Mol Pharm,2017,14:1831-1839.
[13]Abucafy MP,Caetano BL,Chiari-Andreo BG,et al.Supramolecular cyclodextrin-based metal-organic frameworks as efficient carrier for anti-inflammatory drugs[J].Eur J Pharm Biopharm,2018,127:112-119.
[14]He YZ,Zhang W,Guo T,et al.Drug nanoclusters formed in confined nano-cages of CD-MOF:dramatic enhancement of solubility and bioavailability of azilsartan[J].Acta Pharm Sin B,2018.DOI:10.1016/j.apsb.2018.09.003.
[15]Singh V,Guo T,Xu HT,et al.Moisture resistant and biofriendly CD-MOF nanoparticles obtained via cholesterol shielding[J].Chem Commun,2017,53:9246-9249.
[16]Wang SZ,McGuirk CM,d'Aquino A,et al.Metal-organic framework nanoparticles[J].Adv Mater,2018.DOI:10.1002/adma.201800202.
[17]Zhang P,Forsgren J,Str?mme M.Stabilisation of amorphous ibuprofen in upsalite,a mesoporous magnesium carbonate,as an approach to increasing the aqueous solubility of poorly soluble drugs[J].Int J Pharm,2014,472:185-191.
[18]Abd-Elrahman AA,El Nabarawi MA,Hassan DH,et al.Keto-profen mesoporous silica nanoparticles SBA-15 hard gelatin cap-sules:preparation and in vitro/in vivo characterization[J].Drug Deliv,2016,23:3387-3398.