PC208 Subendothelial Matrix-Targeted Liposomal Nanoparticles for Vascular Therapeutics

Vascular intervention results in intimal denudation, exposure of the subendothelial matrix, and subsequent intimal hyperplasia (IH), under the control of numerous remodeling mechanisms. Reduction of IH-induced restenosis may be achieved by manipulation of these remodeling pathways through targeted molecular inhibition. Spatially controlled nanoparticles designed to colocalize to exposed subendothelial matrices could provide an optimal delivery system for targeted vascular therapeutics. To his end, we aimed to develop the framework for a surface-modified liposomal drug delivery platform designed to preferentially bind collagen type IV. Nontargeted control liposomes (NTL) were formed with bulk DOPC-PEG, 30% cholesterol, and 0.1 mol% Rhodamine-DOPE. DSPE-PEG-DBCO lipids were conjugated to peptides previously shown to bind collagen IV via copper-free click chemistry and inserted at 5 mol% to form collagen-targeting liposomes (CTL), either at hydration (PreCTL) or by postinsertion via micellar transfer (PostCTL). Peptide conjugation was confirmed by matrix-assisted laser desorption/ionization time of flight, and liposomes were characterized by dynamic light scattering and electrophoretic mobility. Liposome binding was assayed on collagen IV matrices dried at 3 μg/cm2 and quantified by fluorescence at 0- to 24-hour static 37°C incubation. All liposome formulations exhibited a narrow size distribution (∼100 nm) and neutral-low positive charge. CTLs demonstrated a significant increase in binding vs NTLs (Fig). CTLs demonstrated significant affinity for collagen IV binding in a static environment compared with NTLs. Future studies aim to optimize the binding capacity of CTLs via further lipid modifications and under flow conditions mimicking vessel wall hemodynamics. Considering the efficacy demonstrated here, CTLs show promise as the framework for a spatially-controlled drug delivery platform for future application in targeted vascular therapeutics.