title: Cell-Demanded VEGF Release via Nanocapsules Elicits Different Receptor Activation Dynamics and Enhanced Angiogenesis.
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.
authors.affiliation: Department of Chemical & Biomolecular Engineering, University of California Los Angeles, 420 Westwood Plaza, 5531 Boelter Hall, Los Angeles, CA, 90095, USA.
authors.forename: Suwei
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Chemical & Biomolecular Engineering, University of California Los Angeles, 420 Westwood Plaza, 5531 Boelter Hall, Los Angeles, CA, 90095, USA. tsegura@ucla.edu.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Segura
mesh_terms: D003692:Delayed-Action Preparations / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D055767:Immobilized Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053769:Nanocapsules / Q000737:chemistry*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D055767:Immobilized Proteins; D053769:Nanocapsules; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Growth factor; Protease-sensitive; Sustained release; Wound repair