title: Suppression of neovascularization and experimental arthritis by D-form of anti-flt-1 peptide conjugated with mini-PEG(™).
abstract: 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.
authors.affiliation: Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Seoul, Korea.
authors.forename: Jin-Sun
authors.initials: JS
authors.lastname: Kong
authors.forename: Seung-Ah
authors.initials: SA
authors.lastname: Yoo
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Kang
authors.forename: Wooree
authors.initials: W
authors.lastname: Ko
authors.forename: Sangmin
authors.initials: S
authors.lastname: Jeon
authors.forename: Chi-Bom
authors.initials: CB
authors.lastname: Chae
authors.forename: Chul-Soo
authors.initials: CS
authors.lastname: Cho
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000150:complications / Q000188:drug therapy*; D002210:Caprylates / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000209:etiology; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011509:Proteoglycans; D018709:Statistics, Nonparametric; D013583:Synovial Membrane / Q000098:blood supply / Q000473:pathology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002210:Caprylates; D004338:Drug Combinations; D007797:Laminin; D009842:Oligopeptides; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen; D040281:Vascular Endothelial Growth Factor Receptor-1