Liu Yujie, Zhou Panpan, Cao Zeying, Liang Wanhui, Yan Jiazhi, Xu Huipeng, Wu Li, Sun Lixin, Gong Likun, Peng Can, Guo Tao, Wang Caifen, Zhang Jiwen
School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China; Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
Center for Drug Delivery System, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; School of Pharmacy, Shenyang Pharmaceutical University, Wenhua Road 103, Shenyang 110016, China.
Int J Pharm. 2022 May 10;619:121685. doi: 10.1016/j.ijpharm.2022.121685. Epub 2022 Mar 19.
The inclusion and nanocluster formed in cyclodextrin-metal organic framework (CD-MOF) make it a remarkable vehicle in improving the solubility and bioavailability of insoluble drugs, but rarely in elongation of drug release kinetics. In this research, an insoluble compound, 18β-glycyrrhetinic acid (GA), encapsulated in CD-MOF (GA@nano-CD-MOF) had prominent effects in the treatment of bleomycin-induced idiopathic pulmonary fibrosis in rats with an enhanced bioavailability by 6.8 times. The solubility of GA@nano-CD-MOF was 7780 times higher than that of GA, which was explained by the solubility parameter of amorphous cells constructed in silico simulation. CD-MOF imparted GA unique biphasic release kinetics, namely, GA released instantly to 52% and slowly released to 100% for a period of 5 days, which made the drug loaded particles much more flexible in pharmaceutical applications. The distribution of GA molecules in CD-MOF and drug loading priority obtained by molecular docking illustrated the formation of biphasic release mode at the molecular level combined with other characterizations of SEM, PXRD, TGA and DSC. In conclusion, CD-MOF has a unique effect to simultaneously solubilize an insoluble drug and extend its release for days as payload in highly soluble particles of γ-cyclodextrin metal-organic frameworks, which broaden the applications of drugs in specific treatment and then enhance the therapeutic effects.
环糊精-金属有机框架（CD-MOF）中形成的包合物和纳米簇使其成为提高难溶性药物溶解度和生物利用度的卓越载体，但在延长药物释放动力学方面却鲜有成效。在本研究中，包裹于CD-MOF中的难溶性化合物18β-甘草次酸（GA）（GA@纳米-CD-MOF）对博来霉素诱导的大鼠特发性肺纤维化具有显著治疗效果，其生物利用度提高了6.8倍。GA@纳米-CD-MOF的溶解度比GA高7780倍，这可通过计算机模拟构建的无定形细胞的溶解度参数来解释。CD-MOF赋予GA独特的双相释放动力学，即GA立即释放52%，并在5天内缓慢释放至100%；这使得载药颗粒在药物应用中更加灵活。通过分子对接获得的GA分子在CD-MOF中的分布及药物负载优先级，结合扫描电子显微镜（SEM）、粉末X射线衍射（PXRD）、热重分析（TGA）和差示扫描量热法（DSC）的其他表征，在分子水平上阐明了双相释放模式的形成。总之，CD-MOF具有独特作用，能同时溶解难溶性药物，并作为γ-环糊精金属有机框架高溶性颗粒中的有效载荷将其释放延长数天，这拓宽了药物在特定治疗中的应用范围，进而增强了治疗效果。
