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A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165)

Nature Chemistry volume 9, pages 715–722 (2017)Cite this article

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Abstract

Protein affinity reagents are widely used in basic research, diagnostics and separations and for clinical applications, the most common of which are antibodies. However, they often suffer from high cost, and difficulties in their development, production and storage. Here we show that a synthetic polymer nanoparticle (NP) can be engineered to have many of the functions of a protein affinity reagent. Polymer NPs with nM affinity to a key vascular endothelial growth factor (VEGF165) inhibit binding of the signalling protein to its receptor VEGFR-2, preventing receptor phosphorylation and downstream VEGF165-dependent endothelial cell migration and invasion into the extracellular matrix. In addition, the NPs inhibit VEGF-mediated new blood vessel formation in Matrigel plugs in vivo. Importantly, the non-toxic NPs were not found to exhibit off-target activity. These results support the assertion that synthetic polymers offer a new paradigm in the search for abiotic protein affinity reagents by providing many of the functions of their protein counterparts.

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Figure 1: The functional and sulfonate and sulfated monomers used for nanoparticle synthesis and a schematic showing the general synthesis of polymer NPs and their chemical composition.
Figure 2: Screening of polymer nanoparticles interacting with VEGF165.
Figure 3: In vitro VEGF-inhibition experiment and comparison with heparin.
Figure 4: Anti-angiogenic effect of NPs.
Figure 5: Schematic images of the interaction of heparins and VEGF165 with NPs of various compositions.

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Acknowledgements

Financial support from the University of California Cancer Research Coordinating Committee and the National Science Foundation (DMR-1308363) is gratefully acknowledged. This research was also supported by a Grant-in-Aid for JSPS Postdoctoral Fellowships for Research Abroad (25-426), Grant-in-Aid for MEXT (23111716 and 25107726), Grant-in-Aid for Young Scientists (A) (23685027), The Kurata Memorial Hitachi Science and Technology Foundation and The Uehara Memorial Foundation. We thank T. Ozeki for help with QCM measurements.

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Authors and Affiliations

  1. Department of Medical Biochemistry, Graduate Division of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, Shizuoka, 422-8526, Japan

    Hiroyuki Koide, Ai Okajima, Saki Ariizumi, Yudai Narita & Naoto Oku

  2. Department of Chemistry, University of California Irvine, Irvine, 92697, California, USA

    Hiroyuki Koide, Keiichi Yoshimatsu, Shih-Hui Lee, Yusuke Yonamine, Adam C. Weisman & Kenneth J. Shea

  3. Department of Chemical Engineering, Kyushu University, 744 Motooka, Fukuoka, 819-0395, Japan

    Yu Hoshino, Yuri Nishimura & Yoshiko Miura

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  1. Hiroyuki Koide
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Contributions

H.K., K.Y., K.J.S., Y.H., N.O. and Y.M. designed the research and H.K. and Y.H. designed the experiments. Y.H., Y.N., and Y.M. synthesized GlcNAc monomers. H.K, K.Y., A.W., S.-H.L. and Y.Y. performed the binding assay with QCM and synthesized NPs. Y.N. took TEM pictures of the NPs. H.K., A.O. and S.A. preformed the in vitro assay with supervision from N.O.; H.K., K.Y., Y.M., Y.H., N.O. and K.J.S. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Naoto Oku, Yoshiko Miura or Kenneth J. Shea.

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The authors declare no competing financial interests.

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Koide, H., Yoshimatsu, K., Hoshino, Y. et al. A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165). Nature Chem 9, 715–722 (2017). https://doi.org/10.1038/nchem.2749

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