Research Paper

Pharmaceutical Research

, Volume 25, Issue 12, pp 2786-2798

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

  • Kyeongsoon ParkAffiliated withBiomedical Research Center, Korea Institute of Science and Technology
  • , Yoo-Shin KimAffiliated withDepartment of Biochemistry and Cell Biology and Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
  • , Gee Young LeeAffiliated withCollege of Pharmacy, Seoul National University
  • , Rang-Woon ParkAffiliated withDepartment of Biochemistry and Cell Biology and Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
  • , In-San KimAffiliated withDepartment of Biochemistry and Cell Biology and Cell and Matrix Research Institute, School of Medicine, Kyungpook National University
  • , Sang Yoon KimAffiliated withDepartment of Otolaryngology–Head and Neck Surgery, Asan Medical Center, College of Medicine, University of Ulsan
  • , Youngro ByunAffiliated withCollege of Pharmacy, Seoul National University Email author 

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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

angiogenesis heparin derivative lithocholic acid RGD SCC7