Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan.

Yuanzhi HE; Wei Zhang; Tao Guo; Guoqing Zhang; Wei Qin; Liu Zhang; Caifen Wang; Weifeng Zhu; Ming Yang; Xiaoxiao HU; Vikramjeet Singh; Li WU; Ruxandra Gref; Jiwen Zhang

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Drug nanoclusters formed in confined nano-cages of CD-MOF: dramatic enhancement of solubility and bioavailability of azilsartan.

Author: Yuanzhi HE ¹ ; Wei ZHANG ² ; Tao GUO ² ; Guoqing ZHANG ² ; Wei QIN ¹ ; Liu ZHANG ² ; Caifen WANG ² ; Weifeng ZHU ¹ ; Ming YANG ¹ ; Xiaoxiao HU ² ; Vikramjeet SINGH ³ ; Li WU ² ; Ruxandra GREF ³ ; Jiwen ZHANG ¹
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1. Key Laboratory of Modern Preparation of TCM, Ministry of Education, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China.
2. Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China.
3. Institut des Sciences Moléculaires d׳Orsay, UMR 8214 CNRS, Université Paris-Sud, Université Paris-Saclay, Orsay 91400, France.
Publication Type:Journal Article
Keywords: Azilsartan; Bioavailability; Mechanism; Molecular modeling; Nanoclusterization; Solubility; γ-Cyclodextrin metal-organic framework
From: Acta Pharmaceutica Sinica B 2019;9(1):97-106
CountryChina
Language:English
Abstract: 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 -cyclodextrin (-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 -CD pairs, whilst other three AZL molecules formed a nanocluster inside the 1.7 nm sized cavity surrounded by six -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.