Development Of Targeting Nanoparticles Mimicking The Adhesive Properties Of Platelets
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The development of biodegradable nanoparticles as drug delivery vehicles presents an improved avenue for intracellular targeted drug delivery. Biodegradable nanoparticles have demonstrated an ability to provide controllable, sustained drug release in vitro. However, in vivo studies have shown that nanoparticles are not effective at adhering to vascular walls under shear stress. The purpose of this study was to investigate methods to improve cellular uptake and targeting of nanoparticles in activated or inflamed endothelial cells (ECs) under fluid shear stress and to determine whether the material properties of a biodegradable polymer, poly (lactic-co-glycolic) acid (PLGA), affected cellular uptake. The hypothesis for this project was that by mimicking the binding of platelets with activated ECs (glycoprotein Iba (GP Iba)-P-selectin), GP Iba-conjugated nanoparticles could exhibit increased targeting and higher cellular uptake in injured or activated endothelial cells under physiological flow conditions. To test this hypothesis, carboxyl polystyrene nanoparticles loaded with green fluorescent dyes were selected as a model particle. Using confocal microscopy, the study found that conjugation of 100 nm polystyrene nanoparticles with GP Iba significantly increased cellular uptake and targeting under fluid shear stress. To develop therapeutic carriers, biodegradable nanoparticles were developed from PLGA using a standard double emulsion technique. Using microscopy, fluorescent measurement, and protein assays, similar cellular uptake properties were observed for 100 nm PLGA and polystyrene nanoparticles, suggesting that the uptake properties of these nanoparticles in ECs were not strongly affected by their material properties. The study also found that PLGA nanoparticles were able to provide sustained drug release for at least 14 days. Preliminary results from this project demonstrate that our novel platelet-mimicking nanoparticles may be the first step towards developing a targeted, sustained, drug delivery system, with the ability to overcome shear regulated cellular uptake.