Abstract 238: Sub-Endothelial Matrix Targeted Liposomal Nanoparticles For Vascular Therapeutics

Objectives: Vascular intervention results in intimal denudation, exposure of the sub-endothelial 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 co-localize to exposed sub-endothelial 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. Methods: Non-targeted 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 post-insertion via micellar transfer (PostCTL). Peptide conjugation was confirmed by MALDI-TOF, and liposomes were characterized by DLS and electrophoretic mobility. Liposome binding was assayed on collagen IV matrices dried at 3ug/cm 2 and quantified by fluorescence at 0-24hr static 37°C incubation. Results: All liposome formulations exhibited a narrow size distribution (~100nm) and neutral-low positive charge. CTLs demonstrated a significant increase in binding vs. NTLs (Fig1). Conclusions: 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. </jats:p