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, 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.

Protease-degradable microgels for protein delivery for vascularization

“…We attribute this increase in vascularization to 1) sustained release of VEGF from the microgels, and 2) host cell binding to RGD within microgels that provide a scaffold for tissue ingrowth and vascularization. Previous reports have shown that sustained release of VEGF combined with a cell-adhesive biomaterial scaffold are critical driving factors for improved vascularization [21-23]. However, the need for invasive surgery to implant bulk, pre-formed devices limits the translation of these tools to the clinic.…”

Lab-On-A-Chip for the Development of Pro-/Anti-Angiogenic Nanomedicines to Treat Brain Diseases

“…More importantly, they can be specifically functionalized to target particular pathways and sites on the BMECs. They are designed to have greater BBB permeability [2,6,9,11,17,19], stability [5,9], half-life [11,18,82,83] and shelf-life [5], high-site specific targeting [10,14,84], and a controlled load-release of drugs [18,19,21,84,85].…”

“…These carriers can be functionalized with specific peptides and proteins, to exploit the endocytosis pathways and also be targeted to specific regions of brain. Simply by encapsulating the drugs into a nano-capsule, the drug was able to cross the BBB [6,18]. The SLNs are spherical solid lipid cores, that can encapsulate hydrophilic molecules, the core is made of triglycerides, fatty acids and waxes, and their size ranges from 400 to 1000 nm [6].…”

“…Recently, NMs have been investigated for their efficacy in treating brain angiogenesis conditions. These have included nano-capsules, such as solid lipid nanoparticles (SLNs) [4][5][6][7][8], liposomes [9][10][11][12][13][14][15][16], exosomes [17], and others [18], as well as nano-scaffolds made of chitosan [19], polymers [20,21], inorganic nanoparticles (NPs) [22][23][24], etc. (see Table 1).…”

Novel biomaterial strategies for controlled growth factor delivery for biomedical applications

“…Polymer nanocapsules for controlled GF release Nanocapsule-based delivery systems have been extensively studied for biomedical applications because they offer a number of advantages, including low polymer content, high drug encapsulation efficiency, and polymeric shell protection against enzyme degradation (Figure 3f). 109,110 Segura et al 111 have synthesized VEGF-loaded protein nanocapsules by assembling a thin polymer layer around the protein core by in situ free-radical polymerization. The introduction of peptides as crosslinkers to the polymer nanocapsules realized the celldemanded release rate of VEGF by mediating the catalytic hydrolysis of polymer shells via extracellular proteases.…”