title: Prevention effect of orally active heparin conjugate on cancer-associated thrombosis.
abstract: Thrombogenesis is a major cause of morbidity and mortality in cancer patients. Prophylaxis with low-molecular-weight heparin (LMWH) is recommended for cancer patients, but requires non-parenteral delivery methods for long-term treatments. In this study, we sought to generate a new oligomeric-bile acid conjugate of LMWH that can be used for oral delivery. We first synthesized a tetramer of deoxycholic acid (tetraDOCA), which was site-specifically conjugated at the end saccharide of LMWH. When LMWH-tetraDOCA conjugate (LHe-tetraD) was orally administered at a dose of 5 mg/kg in ICR mice, the maximum anti-factor Xa level was increased up to 0.62±0.05 IU/mL without any evidence of liver toxicity, gastrointestinal damage, or thrombocytopenia. The cancer-associated thrombosis was induced in tumor-bearing mice by local heat application, and the fibrin deposition in tumors was evaluated. The oral administration of LHe-tetraD (either a single dose or multiple daily doses for up to 10 days) in mice substantially abolished the coagulation-dependent tropism of fibrinogen in the heated tumors and significantly decreased hemorrhage, compared to the mice treated with saline or subcutaneous injection of LMWH. Thus, the anticoagulation effect of oral LHe-tetraD invokes the benefits of oral delivery and promises to provide an effective and convenient treatment for cancer patients at risk of thrombosis.
authors.affiliation: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.affiliation: College of Pharmacy, Mokpo National University, Mokpo 534-729, South Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Park
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: Department of Molecular and Cellular Biology, School of Medicine, Sungkyunkwan University, Seoul 135-710, South Korea. Electronic address: gyuharyu@gmail.com.
authors.forename: Gyu Ha
authors.initials: GH
authors.lastname: Ryu
authors.affiliation: Research Institute of Pharmaceutical Sciences, 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.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D015951:Factor Xa / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D006494:Heparin Antagonists / Q000494:pharmacology; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D006979:Hyperthermia, Induced / Q000009:adverse effects; D008297:Male; D008813:Mice, Inbred ICR; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000628:therapy; D011479:Protamines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013927:Thrombosis / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D000925:Anticoagulants; D006494:Heparin Antagonists; D006495:Heparin, Low-Molecular-Weight; C521279:LMWH-DOCA conjugate; D011479:Protamines; D003840:Deoxycholic Acid; D005340:Fibrinogen; D015951:Factor Xa
keywords: Anticoagulants; Cancer-associated thrombosis; Heparin conjugate; Oral delivery