Suppression of angiogenesis and tumor growth by orally active deoxycholic acid-heparin conjugate

J Control Release. 2007 Apr 23;118(3):310-7. doi: 10.1016/j.jconrel.2006.12.031. Epub 2007 Jan 12.

Abstract

Heparin, a potent inhibitor of blood coagulation, exhibits antitumoral action in tumor progression such as in angiogenesis and metastasis but is not orally absorbed in the body, making it an attractive candidate as an oral drug for antiangiogenic cancer therapy. We generated LHD or orally active heparin using low molecular weight heparin (LMWH) and deoxycholic acid that is effectively absorbed in the gastrointestinal tract. Using the in vitro endothelial tubular formation and chicken chorioallantoic membrane angiogenesis assay, we found that antiangiogenic activity of this LHD was similar to that of LMWH. From the in vivo Matrigel plugs assay, LHD treated orally could effectively inhibit angiogenesis into the plugs induced by basic fibroblast growth factor, whereas LMWH treated orally could not due to no oral absorption. In addition, when this LHD was orally administered into the tumor bearing mice, it significantly inhibited tumor growth by its antiangiogenic therapeutic mechanism, and when accompanied with doxorubicin, it appeared to have an additive effect. Collectively, LHD having antiangiogenic activity could be orally absorbable and inhibit tumor growth via inhibiting angiogenesis. These findings demonstrate the therapeutic potential of LHD in the clinical trials, which is suggested as a new oral therapeutic remedy for cancer therapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Angiogenesis Inhibitors / administration & dosage*
  • Animals
  • Cell Line, Tumor
  • Chickens
  • Deoxycholic Acid / administration & dosage*
  • Heparin, Low-Molecular-Weight / administration & dosage*
  • Humans
  • Mice
  • Mice, Inbred C3H
  • Neoplasms / drug therapy
  • Neoplasms / physiopathology
  • Neoplasms / prevention & control*
  • Neovascularization, Pathologic / drug therapy
  • Neovascularization, Pathologic / physiopathology
  • Neovascularization, Pathologic / prevention & control*

Substances

  • Angiogenesis Inhibitors
  • Heparin, Low-Molecular-Weight
  • Deoxycholic Acid