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
  • 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: [email protected].
  • 8. Institut de Sciences Moléculaires d'Orsay, Université Paris-Saclay, UMR CNRS 8214, 91400 Orsay Cedex, France. Electronic address: [email protected].
  • 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: [email protected].
PMID: 30528633 DOI: 10.1016/j.ijpharm.2018.11.074
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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