Pharmaceutical Research

, 25:2786

Tumor Endothelial Cell Targeted Cyclic RGD-modified Heparin Derivative: Inhibition of Angiogenesis and Tumor Growth

Authors

  • Kyeongsoon Park
    • Biomedical Research CenterKorea Institute of Science and Technology
  • Yoo-Shin Kim
    • Department of Biochemistry and Cell Biology and Cell and Matrix Research Institute, School of MedicineKyungpook National University
  • Gee Young Lee
    • College of PharmacySeoul National University
  • Rang-Woon Park
    • Department of Biochemistry and Cell Biology and Cell and Matrix Research Institute, School of MedicineKyungpook National University
  • In-San Kim
    • Department of Biochemistry and Cell Biology and Cell and Matrix Research Institute, School of MedicineKyungpook National University
  • Sang Yoon Kim
    • Department of Otolaryngology–Head and Neck Surgery, Asan Medical Center, College of MedicineUniversity of Ulsan
    • College of PharmacySeoul National University
Research Paper

DOI: 10.1007/s11095-008-9643-y

Cite this article as:
Park, K., Kim, Y., Lee, G.Y. et al. Pharm Res (2008) 25: 2786. doi:10.1007/s11095-008-9643-y

Abstracts

Purpose

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 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.

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 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.

Conclusion

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 WORDS

angiogenesisheparin derivativelithocholic acidRGDSCC7

Abbreviations

bFGF

basic fibroblast growth factor

ECM

extracellular matrix

ERK

extracellular signal-regulated kinase

FGFR

fibroblast growth factor receptor

HL

heparin-lithocholic acid

HUVEC

human umbilical vein endothelial cells

MAPK

mitogen-activated protein kinase

SCC7

squamous cell carcinoma

Copyright information

© Springer Science+Business Media, LLC 2008