Suppression of neovascularization and experimental arthritis by D-form of anti-flt-1 peptide conjugated with mini-PEG

• Published in: Angiogenesis (London) 2011-12, Vol.14 (4), p.431-442
• Main Authors: Kong, Jin-Sun, Yoo, Seung-Ah, Kang, Jong-Hoon, Ko, Wooree, Jeon, Sangmin, Chae, Chi-Bom, Cho, Chul-Soo, Kim, Wan-Uk
• Format: Article
• Language: English
• Subjects: Alcoholism and acute alcohol poisoning; Animals; Arthritis, Experimental - complications; Arthritis, Experimental - drug therapy; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Blood and lymphatic vessels; Cancer Research; Caprylates - metabolism; Cardiology; Cardiology. Vascular system; Cell Biology; Chemotaxis - drug effects; Collagen; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Drug Combinations; Endothelial Cells - drug effects; Humans; Immunohistochemistry; Laminin; Medical sciences; Mice; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - etiology; Oligopeptides - chemistry; Oligopeptides - metabolism; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; Oncology; Ophthalmology; Original Paper; Proteoglycans; Statistics, Nonparametric; Synovial Membrane - blood supply; Synovial Membrane - pathology; Toxicology; Umbilical Veins - cytology; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-1 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-1 - metabolism
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-011-9226-0

Extensive angiogenesis in the synoviums is a characteristic pathology of rheumatoid arthritis (RA). We have demonstrated that anti-flt-1 hexapeptide, GNQWFI, specifically inhibits the interaction of VEGF or PlGF with its receptor flt-1 (Yoo et al. [ 13 ]). In this study, we investigate the feasibility of the synthetic D-form of anti-flt-1 hexapeptide conjugated with 8-amino-3,6-dioxaoctanoic acid (mini-PEG ™ ) for treatment of RA. We first modified the structure of anti-flt-1 peptide from the L-form (GNQWFI) to all D-form (gnqwfi; allD) and then conjugated allD with mini-PEG ™ to enhance its stability. The result showed that the allD anti-flt-1 peptide showed an increased stability in the sera without major loss of inhibitory activity. The allD and its mini-PEGylated derivative similarly suppressed wounding migration, chemotaxis, and tube formation of endothelial cells in vitro. However, in the Matrigels assay, the in vivo anti-angiogenic activity of mini-PEGylated allD was stronger than that of native allD or L-form. Moreover, oral and subcutaneous administration of mini-PEGylated allD, but not oral feeding of original L-form, successfully suppressed severity of collagen-induced arthritis. After a single subcutaneous injection, the Cy5-labeled mini-PEGylated allD was found to be distributed systemically and accumulated in arthritic joints of mice, particularly in joints with a severe clinical score. In conclusion, our data suggests that mini-PEGylated allD is more beneficial in the treatment of RA than unmodified anti-flt-1 peptides, since it has increased stability and the possibility of oral delivery, and could be applied to treat angiogenesis-dependent human diseases, including RA.