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High antiangiogenic and low anticoagulant efficacy of orally active low molecular weight heparin derivatives.

Abstract
Heparin, an anticoagulant that is widely used clinically, is also known to bind to several kinds of proteins through electrostatic interactions because of its polyanionic character. These interactions are mediated by the physicochemical properties of heparin such as sequence composition, sulfation patterns, charge distribution, overall charge density, and molecular size. Although this electrostatic character mediates its binding to many proteins related with tumor progression, thereby providing its antiangiogenic property, the administration of heparin for treating cancer is limited in clinical applications due to several drawbacks, such as its low oral absorption, unsatisfactory therapeutic effects, and strong anticoagulant activity which induces hemorrhaging. Here, we evaluated novel, orally active, low molecular weight heparin (LMWH) derivatives (LHD) conjugated with deoxycholic acid (DOCA) that show reduced anticoagulant activity and enhanced antiangiogenic activity. The chemical conjugate of LMWH and DOCA was synthesized by conjugating the amine group of N-deoxycholylethylamine (EtDOCA) with the carboxylic groups of heparin at various DOCA conjugation ratios. The LMWH-DOCA conjugate series (LHD1, LHD1.5, LHD2, and LHD4) were further formulated with poloxamer 407 as a solubilizer for oral administration. An in vitro endothelial tubular formation and in vivo Matrigel plug assay were performed to verify the antiangiogenic potential of LHD. Finally, we evaluated tumor growth inhibition of oral LHD administration in a SCC7 model as well as in A549 human cancer cell lines in a mouse xenograft model. Increasing DOCA conjugation ratios showed decreased anticoagulant activity, eventually to zero. LHD could block angiogenesis in the tubular formation assay and the Matrigel plug assay. In particular, oral administration of LHD4, which has 4 molecules of DOCA per mole of LMWH, inhibited tumor growth in SCC7 mice model as well as A549 mice xenograft model. LHD4 was orally absorbable, showed minimal anticoagulant activity and inhibits tumor growth via antiangiogenesis. These findings demonstrate the therapeutic potential of LHD4 as a new oral anti-cancer drug.
AuthorsJin Woo Park, Ok Cheol Jeon, Sang Kyoon Kim, Taslim Ahmed Al-Hilal, Shun Ji Jin, Hyun Tae Moon, Victor C Yang, Sang Yoon Kim, Youngro Byun
JournalJournal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 148 Issue 3 Pg. 317-26 (Dec 20 2010) ISSN: 1873-4995 [Electronic] Netherlands
PMID20869408 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2010 Elsevier B.V. All rights reserved.
Chemical References
  • Angiogenesis Inhibitors
  • Anticoagulants
  • Heparin, Low-Molecular-Weight
  • LMWH-DOCA conjugate
  • Deoxycholic Acid
Topics
  • Administration, Oral
  • Angiogenesis Inhibitors (administration & dosage, chemistry, pharmacology, therapeutic use)
  • Animals
  • Anticoagulants (administration & dosage, chemistry, pharmacology, therapeutic use)
  • Cell Line, Tumor
  • Cell Survival (drug effects)
  • Deoxycholic Acid (administration & dosage, analogs & derivatives, chemistry, pharmacology, therapeutic use)
  • Heparin, Low-Molecular-Weight (administration & dosage, analogs & derivatives, chemistry, pharmacology, therapeutic use)
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Nude
  • Neoplasms (drug therapy, pathology)
  • Solubility

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