Oligomeric bile acid-mediated oral delivery of low molecular weight heparin

Taslim A. Al-Hilal, Jooho Park, Farzana Alam, Seung Woo Chung, Jin Woo Park, Kwangmeyung Kim, Ick Chan Kwon, In San Kim, Sang Yoon Kim, Youngro Byun

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33 Citations (Scopus)

Abstract

Intestinal transporters are limited to the transport of small molecular substrates. Here, we describe the development of apical sodium-dependent bile acid transporter (ASBT)-targeted high-affinity oligomeric bile acid substrates that mediate the transmembrane transport of low molecular weight heparin (LMWH). Several oligomers of deoxycholic acid (oligoDOCA) were synthesized to investigate the substrate specificity of ASBT. To see the binding of oligoDOCA on the substrate-binding pocket of ASBT, molecular docking was used and the dissociation rate constants (KD) were measured using surface plasmon resonance. The KD for tetrameric DOCA (tetraDOCA) was 50-fold lower than that for monomeric DOCA, because tetraDOCA interacted with several hydrophobic grooves in the substrate-binding pocket of ASBT. The synthesized oligoDOCA compounds were subsequently chemically conjugated to macromolecular LMWH. In vitro, tetraDOCA-conjugated LMWH (LHe-tetraD) had highest selectivity for ASBT during its transport. Orally administered LHe-tetraD showed remarkable systemic anticoagulation activity and high oral bioavailability of 33.5 ± 3.2% and 19.9 ± 2.5% in rats and monkeys, respectively. Notably, LHe-tetraD successfully prevented thrombosis in a rat model of deep vein thrombosis. These results represent a major advancement in ASBT-mediated LMWH delivery and may facilitate administration of many important therapeutic macromolecules through a non-invasive oral route.

Original languageEnglish
Pages (from-to)17-24
Number of pages8
JournalJournal of Controlled Release
Volume175
Issue number1
DOIs
Publication statusPublished - 2014 Feb 10

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Keywords

  • Bile acid conjugate
  • Bile acid transporter
  • Heparin
  • Oral delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Al-Hilal, T. A., Park, J., Alam, F., Chung, S. W., Park, J. W., Kim, K., Kwon, I. C., Kim, I. S., Kim, S. Y., & Byun, Y. (2014). Oligomeric bile acid-mediated oral delivery of low molecular weight heparin. Journal of Controlled Release, 175(1), 17-24. https://doi.org/10.1016/j.jconrel.2013.12.001