title: N-acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and improves delivery of a small molecule p38 inhibitor for post-infarct healing.
abstract: An estimated 985,000 new myocardial infarctions will occur in the USA 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 limits existing options that rely on phagocytosis. Recently, the sugar N-acetylglucosamine (GlcNAc) was shown 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 as measured by intracellular activated fluorescence. When delivered in vivo following ischemia-reperfusion injury, GlcNAc-decorated particles loaded with the p38 inhibitor SB239063 reduced apoptotic events and 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 reduce the large amount of CM cell death following myocardial injury.
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering, Emory University, Atlanta, GA 30322, USA.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Gray
authors.forename: Paolin
authors.initials: P
authors.lastname: Che
authors.forename: Milton
authors.initials: M
authors.lastname: Brown
authors.forename: Xinghai
authors.initials: X
authors.lastname: Ning
authors.forename: Niren
authors.initials: N
authors.lastname: Murthy
authors.forename: Michael E
authors.initials: ME
authors.lastname: Davis
mesh_terms: D000117:Acetylglucosamine / Q000737:chemistry*; D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage*; D004337:Drug Carriers; D007093:Imidazoles / Q000008:administration & dosage*; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000201:enzymology*; D053758:Nanoparticles; D011108:Polymers / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002317:Cardiovascular Agents; D004337:Drug Carriers; D007093:Imidazoles; D011108:Polymers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C517410:poly(cyclohexane-1,4-diyl acetone dimethylene ketal); D048051:p38 Mitogen-Activated Protein Kinases; C406525:SB 239063; D000117:Acetylglucosamine