Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been a...Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile γ-cyclodextrin(γ-CD) metal-organic framework(CD-MOF) large molecular cages in which azilsartan(AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague–Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering(SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy(SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the γ-CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six γ-CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.展开更多
基金financial support from the Project funded by the National Science and Technology Major Projects for the Major New Drugs Innovation and Development (2018ZX09721002-009, China)Strategic Priority Research Program of Chinese Academy of Sciences (XDA12050307)+1 种基金National Natural Science Foundation of China (81430087)China Postdoctoral Science Foundation (2017M610284)
文摘Tremendous efforts have been devoted to the enhancement of drug solubility using nanotechnologies, but few of them are capable to produce drug particles with sizes less than a few nanometers. This challenge has been addressed here by using biocompatible versatile γ-cyclodextrin(γ-CD) metal-organic framework(CD-MOF) large molecular cages in which azilsartan(AZL) was successfully confined producing clusters in the nanometer range. This strategy allowed to improve the bioavailability of AZL in Sprague–Dawley rats by 9.7-fold after loading into CD-MOF. The apparent solubility of AZL/CD-MOF was enhanced by 340-fold when compared to the pure drug. Based on molecular modeling, a dual molecular mechanism of nanoclusterization and complexation of AZL inside the CD-MOF cages was proposed, which was confirmed by small angle X-ray scattering(SAXS) and synchrotron radiation-Fourier transform infrared spectroscopy(SR-FTIR) techniques. In a typical cage-like unit of CD-MOF, three molecules of AZL were included by the γ-CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six γ-CDs. This research demonstrates a dual molecular mechanism of complexation and nanoclusterization in CD-MOF leading to significant improvement in the bioavailability of insoluble drugs.
