title: Physicochemical conjugation with deoxycholic acid and dimethylsulfoxide for heparin oral delivery.
abstract: Heparin, as therapeutic medications, cannot be administered orally because of its hydrophilic and high molecular weight. Here, we present a new technology to enhance the absorption of heparin in the intestine through its chemical conjugation with deoxycholic acid (DOCA) that can interact with bile acid transporter in the intestine. For the ampiphilic property and complete dissolution, the modified heparin was physically complexed with dimethylsulfoxide (DMSO). The DOCA-conjugated heparin could form nanoparticles in aqueous solution, whereas it was completely dissolved when treated with above 10% DMSO solution. Molecular dynamics computation study and two-dimensional homonulcear (1)H nuclear overhauser effect spectroscopy (NOESY) NMR spectra demonstrated that one heparin molecule was chemically conjugated with two DOCA molecules that were physically interacted with six DMSO molecules within 4 Å via hydrophobic interactions and partly via hydrogen bonding. Its therapeutic efficacy was also pharmaceutically analyzed. When the DMSO-bound DOCA-conjugated heparin was orally administered into mice, its therapeutic efficacy was enhanced according to the amount of bound DMSO. Also, after oral administration of fluorescence-labeled DMSO-bound DOCA-conjugated heparin, it was circulated in the whole body for above 2 h. However, the DOCA-conjugated heparin without DMSO binding was fast eliminated after oral absorption. This study demonstrates that the interaction of structural constraints, DOCA and DMSO, with heparin can serve as a platform technology for potential macromolecule oral delivery.
authors.affiliation: WCU Department of Molecular Medicine and Biopharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Sang Kyoon
authors.initials: SK
authors.lastname: Kim
authors.forename: June
authors.initials: J
authors.lastname: Huh
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Lee
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Moon
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D003840:Deoxycholic Acid / Q000737:chemistry*; D004121:Dimethyl Sulfoxide / Q000737:chemistry*; D006493:Heparin / Q000008:administration & dosage* / Q000097:blood / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D056004:Molecular Dynamics Simulation
chemical_list: D000925:Anticoagulants; D003840:Deoxycholic Acid; D006493:Heparin; D004121:Dimethyl Sulfoxide