Abstract P164: N-acetylglucosamine Conjugated to Nanoparticles Enhances Myocyte Uptake and Improves Delivery of a Small Molecule P38 Inhibitor for Postinfarct Healing
An estimated 985,000 new myocardial infarctions (MI) will occur in the U.S. in 2011. While many will survive the initial insult, the early damage will eventually lead to heart failure for which the only definitive cure is transplantation. Cardiomyocyte (CM) apoptosis is a large contributor to cardiac dysfunction, and although potential therapeutic molecules exist to inhibit apoptotic pathways, drug delivery methods are lacking. This damage is largely regional and thus localized delivery of therapeutics holds great potential. However, CMs are relatively non-phagocytic, which precludes existing delivery schemes using polymeric particles that target phagocytic cells. Recently, the carbohydrate N-acetyl-glucosamine (GlcNAc) was discovered to be bound and internalized by CMs, providing a potential mechanism for drug delivery. Here we demonstrate efficacy of a drug delivery system comprising a drug-loaded biodegradable polyketal nanoparticle that is surface-decorated with GlcNAc. Inclusion of the sugar enhanced uptake by CMs in vitro as measured by intracellular activated fluorescence. When delivered in vivo following ischemia-reperfusion injury, GlcNAc-decorated particles loaded with the p38 inhibitor SB239063 reduced infarct size and improved acute cardiac function. This was in contrast to our published data demonstrating no acute effect of non-sugar decorated, p38 inhibitor-loaded particles. These data suggest a novel therapeutic option to enhance uptake of drug-loaded nanoparticles to CMs, and perhaps to reduce the large amount of CM cell death following myocardial injury.
- © 2011 by American Heart Association, Inc.