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

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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.

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Acknowledgments

We thank all the members of the Institute of Bone and Joint Diseases at the Catholic University of Korea. This work was supported by grants from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs (No. A092258 and No. A084948), and National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (R33-2008-000-10064-0 and 2009-0080087).

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Authors and Affiliations

  1. Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Seoul, Korea

    Jin-Sun Kong, Seung-Ah Yoo, Chul-Soo Cho & Wan-Uk Kim

  2. Postech-Catholic Biomedical Engineering Institute, Catholic University of Korea, Seoul, Korea

    Jong-Hoon Kang & Chi-Bom Chae

  3. Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, Korea

    Wooree Ko & Sangmin Jeon

  4. Division of Rheumatology, Department of Internal Medicine, School of Medicine, Catholic University of Korea, St. Vincent’s Hospital, 93 Chi-Dong, Suwon, 442-723, South Korea

    Chul-Soo Cho & Wan-Uk Kim

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  1. Jin-Sun Kong
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  2. Seung-Ah Yoo
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Correspondence to Wan-Uk Kim.

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Jin-Sun Kong and Seung-Ah Yoo contributed equally to this work.

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Kong, JS., Yoo, SA., Kang, JH. et al. Suppression of neovascularization and experimental arthritis by D-form of anti-flt-1 peptide conjugated with mini-PEG™ . Angiogenesis 14, 431–442 (2011). https://doi.org/10.1007/s10456-011-9226-0

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  • DOI: https://doi.org/10.1007/s10456-011-9226-0

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