title: Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid.
abstract: Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight heparin derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3 ± 2.89%) and prolonged the mean residence time (7.5 ± 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2 ± 3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
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: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Department of Biomedical Engineering, Computer and Biomedical Engineering, Medical Industry Techno Tower R307, Yonsei University, Wonju, Gangwon 220-710, South Korea.
authors.forename: Donghyun
authors.initials: D
authors.lastname: Seo
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Foyez
authors.initials: F
authors.lastname: Mahmud
authors.affiliation: Department of Biomedical Engineering, Computer and Biomedical Engineering, Medical Industry Techno Tower R307, Yonsei University, Wonju, Gangwon 220-710, South Korea.
authors.forename: Han Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: 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.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea; Research Institute of Pharmaceutical Sciences, College of Pharmacy, 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; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001682:Biological Availability; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D003840:Deoxycholic Acid / Q000737:chemistry / Q000494:pharmacology*; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007422:Intestines / Q000187:drug effects / Q000502:physiology; D008297:Male; D009369:Neoplasms / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010084:Oxidation-Reduction; D017207:Rats, Sprague-Dawley; D018874:Spheroids, Cellular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D006495:Heparin, Low-Molecular-Weight; C580866:LHT7 compound; D003840:Deoxycholic Acid; D013656:Taurocholic Acid; D006493:Heparin
keywords: Angiogenesis inhibitor; Deoxycholic acid; Heparin conjugate; Oral delivery