Tumor Endothelial Cell Targeted Cyclic RGD-modified Heparin Derivative: Inhibition of Angiogenesis and Tumor Growth
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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.
To evaluate antiangiogenic activity of cRGD-HL, we performed tests on endothelial cell adhesion and migration to vitronectin, tube formation, binding affinity to purified αvβ3 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.
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 αvβ3 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 αvβ3-mediated interaction, resulting in the enhanced antitumoral activity against SCC7 tumor.
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.
KEY WORDSangiogenesis heparin derivative lithocholic acid RGD SCC7
basic fibroblast growth factor
extracellular signal-regulated kinase
fibroblast growth factor receptor
human umbilical vein endothelial cells
mitogen-activated protein kinase
squamous cell carcinoma
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