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  2. A "Ship-in-a-Bottle" strategy to create folic acid nanoclusters inside the nanocages of γ-cyclodextrin metal-organic frameworks

A "Ship-in-a-Bottle" strategy to create folic acid nanoclusters inside the nanocages of γ-cyclodextrin metal-organic frameworks

  • Int J Pharm. 2019 Feb 10;556:89-96. doi: 10.1016/j.ijpharm.2018.11.074.
Jian Xu 1 Li Wu 2 Tao Guo 3 Guoqing Zhang 4 Caifen Wang 3 Haiyan Li 3 Xue Li 5 Vikramjeet Singh 6 Weidong Chen 7 Ruxandra Gref 8 Jiwen Zhang 9
Affiliations

Affiliations

  • 1 Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China; School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Ministry of Education, Yantai University, Yantai 264005, China.
  • 3 Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China.
  • 4 Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China; School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 5 Institut de Sciences Moléculaires d'Orsay, Université Paris-Saclay, UMR CNRS 8214, 91400 Orsay Cedex, France.
  • 6 Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China; Institut de Sciences Moléculaires d'Orsay, Université Paris-Saclay, UMR CNRS 8214, 91400 Orsay Cedex, France.
  • 7 School of Pharmaceutical Sciences, Anhui University of Chinese Medicine, Hefei 230012, China. Electronic address: anzhongdong@126.com.
  • 8 Institut de Sciences Moléculaires d'Orsay, Université Paris-Saclay, UMR CNRS 8214, 91400 Orsay Cedex, France. Electronic address: ruxandra.gref@u-psud.fr.
  • 9 Center for Drug Delivery Systems, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: jwzhang@simm.ac.cn.
Abstract

Assembled between γ-cyclodextrins (CD) and potassium ions, γ-cyclodextrin metal-organic frameworks (CD-MOF) create spatially extended and ordered cage-like structures. Herein, it was demonstrated that folic acid (FA), a model molecule, could be densely packed inside CD-MOF reaching 2:1 FA:CD molar ratio. This "Ship-in-a-Bottle" strategy leads to a 1450 fold increase of the apparent solubility of FA. Moreover, the bioavailability of FA inside CD-MOF in rats was enhanced by a factor of 1.48 as compared to free FA. The unique mechanism of FA incorporation in the CD-MOF 3D network was also explored, which was different from the conventional CD inclusion complexation. Taylor dispersion investigations indicated that FA was incorporated on the basis of a two-component model, which was further supported by a set of complementary methods, including SEM, XRPD, BET, SR-FTIR, SAXS and molecular simulation. The hypothesized mechanism suggested that: i) tiny FA nanoclusters formed inside the hydrophilic cavities and onto the surface of CD-MOF and ii) FA was included inside dual-CD units in CD-MOF. In a nutshell, this dual incorporation mechanism is an original approach to dramatically increase the drug apparent solubility and bioavailability, and could be a promising strategy for other poorly soluble drugs.

Keywords

Drug loading; Folic acid; Nanoclusters; Ship-in-a-Bottle; γ-Cyclodextrin metal-organic frameworks.

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