Al-Hilal, Taslim A. Park, Jooho Alam, Farzana Chung, Seung Woo Park, Jin Woo Kim, Kwangmeyung Kwon, Ick Chan Kim, In-San Kim, Sang Yoon Byun, Youngro 2024-01-20T10:31:15Z 2024-01-20T10:31:15Z 2021-09-05 2014-02-10 0168-3659 https://pubs.kist.re.kr/handle/201004/127097 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. English ELSEVIER SCIENCE BV DEOXYCHOLIC-ACID DRUG-DELIVERY TRANSPORTER SLC10A2 ABSORPTION ANTICOAGULANT STRATEGIES CONJUGATE TOPOLOGY DOMAINS AGENT Oligomeric bile acid-mediated oral delivery of low molecular weight heparin Article 10.1016/j.jconrel.2013.12.001 1 JOURNAL OF CONTROLLED RELEASE, v.175, pp.17 - 24 JOURNAL OF CONTROLLED RELEASE 175 17 24 scie scopus 000330121200003 2-s2.0-84891528616 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article DEOXYCHOLIC-ACID DRUG-DELIVERY TRANSPORTER SLC10A2 ABSORPTION ANTICOAGULANT STRATEGIES CONJUGATE TOPOLOGY DOMAINS AGENT Oral delivery Heparin Bile acid conjugate Bile acid transporter