Journal
JOURNAL OF CONTROLLED RELEASE
Volume 175, Issue -, Pages 17-24Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2013.12.001
Keywords
Oral delivery; Heparin; Bile acid conjugate; Bile acid transporter
Funding
- World Class University (WCU) program [R31-2008-000-10103]
- Converging Research Center Program [2012 K-001398]
- Bio & Medical Technology Development Program through the National Research Foundation of Korea (NRF) [2012028833]
- Ministry of Education, Science and Technology, Republic of Korea
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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 (K-D) 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. (C) 2013 Published by Elsevier B.V.
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