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

被引:44
作者
Lee, Dong Yun
Kim, Sang Kyoon
Kim, Yoo Shin
Son, Dai Hyun
Nam, Jong Hee
Kim, In San
Park, Rang Woon
Kim, Sang Yoon
Byun, Youngro
机构
[1] Seoul Natl Univ, Coll Pharm, Seoul 151742, South Korea
[2] Gwangju Inst Sci & Technol, Dept Mat Sci & Engn, Kwangju 500712, South Korea
[3] Kyungpook Natl Univ, Sch Med, Dept Biochem, Taegu 700422, South Korea
[4] Univ Ulsan, Asan Med Ctr, Dept Otolaryngol, Seoul 138736, South Korea
[5] Chonnam Natl Univ, Sch Med, Dept Pathol, Kwangju 500757, South Korea
关键词
angiogenesis; chemotherapy; drug delivery; heparin; deoxycholic acid; growth factor;
D O I
10.1016/j.jconrel.2006.12.031
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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. (c) 2007 Elsevier B.V. All rights reserved.
引用
收藏
页码:310 / 317
页数:8
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