title: Oligomeric bile acid-mediated oral delivery of low molecular weight heparin.
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.
authors: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors: Taslim A
authors: TA
authors: Al-Hilal
authors: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors: Jooho
authors: J
authors: Park
authors: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors: Farzana
authors: F
authors: Alam
authors: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors: Seung Woo
authors: SW
authors: Chung
authors: College of Pharmacy, Mokpo National University, Mokpo 534-729, South Korea.
authors: Jin Woo
authors: JW
authors: Park
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors: Kwangmeyung
authors: K
authors: Kim
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors: Ick Chan
authors: IC
authors: Kwon
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 700-422, South Korea.
authors: In-San
authors: IS
authors: Kim
authors: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea; Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors: Sang Yoon
authors: SY
authors: Kim
authors: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea. Electronic address: yrbyun@snu.ac.kr.
authors: Youngro
authors: Y
authors: Byun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002460:Cell Line; D003840:Deoxycholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008252:Macaca fascicularis; D008297:Male; D008958:Models, Molecular; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters / Q000378:metabolism*; D020246:Venous Thrombosis / Q000517:prevention & control
chemical_list: D000925:Anticoagulants; D004337:Drug Carriers; D006495:Heparin, Low-Molecular-Weight; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; D003840:Deoxycholic Acid; C071908:sodium-bile acid cotransporter
keywords: Bile acid conjugate; Bile acid transporter; Heparin; Oral delivery