Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis.

TitleCell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsS Zhu, and T Segura
JournalAnnals of Biomedical Engineering
Volume44
Issue6
Start Page1983
Pagination1983 - 1992
Date Published06/2016
Abstract

Although the delivery of vascular endothelial growth factor (VEGF) with extended release profiles has consistently shown beneficial therapeutic effects compared with bolus delivery, [Martino, M. M., F. Tortelli, M. Mochizuki, S. Traub, D. Ben-David, G. A. Kuhn, R. Muller, E. Livne, S. A. Eming, and J. A. Hubbell. Sci. Transl. Med. 3(100):100ra189, 2011; Martino, M. M., P. S. Briquez, A. Ranga, M. P. Lutolf, and J. A. Hubbell. Proc. Natl. Acad. Sci. USA. 110(12):4563-4568, 2013; Amiram, M., K. M. Luginbuhl, X. Li, M. N. Feinglos, and A. Chilkoti. Proc. Natl. Acad. Sci. USA. 110(8):2792-2797, 2013] it remains unclear if the reason is solely due to the physical availability and the reduced degradation of the protein. Here we studied the activation of VEGF receptor 2 (VR-2) by sustained released VEGF compared with bolus delivered VEGF to unveil that sustained delivery system alters the dynamics of receptor activation and affects the actions of cells between sprouting and proliferation. We utilized a protein nanocapsule delivery strategy that releases VEGF as mediated by extracellular proteases. These protein nanocapsules were synthesized through an aqueous assembly of a nanogel-peptide shell around the protein, leading to one to two proteins encapsulated per nanocapsule. Receptor activation studies revealed differential dynamics of receptor activation for slowly released VEGF compared with bolus delivered VEGF. As expected sustained released VEGF via nanocapsules resulted in enhanced vascular sprouting in vitro and in vivo. These studies demonstrate the physical presentation of VEGF, in this case of a slow release with time, can affect its molecular mechanism of actions and cause alterations in cellular responses and therapeutic outcomes.

DOI10.1007/s10439-016-1581-y
Short TitleAnnals of Biomedical Engineering