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

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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
Issue number1
StatePublished - 10 Feb 2014

Bibliographical note

Funding Information:
We thank Ms Eun Jung Kang for the technical support with confocal imaging. This study was supported by a grant from the World Class University (WCU) program (grant no. R31-2008-000-10103 ), the Converging Research Center Program (grant no. 2012 K-001398 ) and the Bio & Medical Technology Development Program (grant no. 2012028833 ) through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Republic of Korea and Mediplex Corp., Korea .


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


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