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

Title
Oligomeric bile acid-mediated oral delivery of low molecular weight heparin
Authors
Taslim A. Al-Hilal박주호Farzana Alam정승우박진우김광명권익찬김인산김상윤변영로
Keywords
Oral delivery; Heparin; Bile acid conjugate; Bile acid transporter
Issue Date
2014-02
Publisher
Journal of controlled release
Citation
VOL 175, 17-24
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.
URI
http://pubs.kist.re.kr/handle/201004/47257
ISSN
01683659
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KIST Publication > Article
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