Tumor endothelial cell targeted cyclic RGD-modified heparin derivative: inhibition of angiogenesis and tumor growth.
OBJECTIVE
We prepared tumor endothelium targeted cRGD-modified heparin derivative (cRGD-HL) by coupling heparin-lithocholic acid (HL) with cRGDyK, and evaluated inhibition effects of cRGD-HL on angiogenesis and tumor growth.


METHODS
To evaluate antiangiogenic activity of cRGD-HL, we performed tests on endothelial cell adhesion and migration to vitronectin, tube formation, binding affinity to purified alpha(v)beta(3) integrin, and in vivo Matrigel plug assay. The antitumor activity of cRGD-HL was also evaluated by monitoring tumor growth and microvessel formation in squamous cell carcinoma (SCC7) tumor.


RESULTS
The cRGD-HL significantly inhibited adhesion and migration of endothelial cells to vitronectin, and tubular structures of endothelial cells. Compared to cRGDyK and HL, cRGD-HL has high binding affinity to purified alpha(v)beta(3) integrin. The enhanced antiangiogenic effect of cRGD-HL was confirmed in Matrigel assay by showing the significant inhibition of bFGF-driven angiogenesis and blood vessel formation. It was thought that potent antiangiogenic effect of cRGD-HL was probably due to the interference of alpha(v)beta(3)-mediated interaction, resulting in the enhanced antitumoral activity against SCC7 tumor.


CONCLUSIONS
These results demonstrated that cRGD-modified heparin derivative enhanced anti-angiotherapeutic effects against solid tumor, and therefore, it could be applied to treat various cancers and angiogenic diseases as a potent angiogenesis inhibitor.
Park
Kyeongsoon
K
Biomedical Research Center, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul, South Korea. kspark@kist.re.kr
Kim
Yoo-Shin
YS
Lee
Gee Young
GY
Park
Rang-Woon
RW
Kim
In-San
IS
Kim
Sang Yoon
SY
Byun
Youngro
Y
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects*; D006493:Heparin / Q000031:analogs & derivatives*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008095:Lithocholic Acid / Q000494:pharmacology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D008095:Lithocholic Acid; C047981:arginyl-glycyl-aspartic acid; D006493:Heparin