The effect of intramural delivery of polymeric nanoparticles loaded with the antiproliferative 2-aminochromone U-86983 on neointimal hyperplasia development in balloon-injured porcine coronary arteries

Abstract Applying local drug delivery techniques in treating restenosis with antiproliferative agents may prove useful in enhancing drug efficacy while minimizing inherent systemic toxicity. Using direct intramural delivery of drug-loaded nanoparticles (U-86NP) composed of the biodegradable co-polymer polylactic-polyglycolic acid (PLGA), we evaluated the in vivo antiproliferative effect of a novel 2-aminochromone, U-86983, in a porcine model of coronary artery neointimal hyperplasia. In vitro, PLGA nanoparticles proved a suitable carrier for U-86983, promoting the gradual release of biologically active drug over a 2-week period. A series of acute canine and porcine experiments subsequently clarified such delivery conditions as catheter device, nanoparticle surface modification, and suspension concentration that maximized U-86NP retention in balloon-injured arterial segments. A chronic efficacy study implementing these delivery conditions was then performed in domestic feeder pigs. Site-specific delivery of U-86NP significantly reduced neointimal hyperplasia in severely balloon-injured porcine coronary arteries but also increased the incidence of medial dissection at the treated site. Delivery conditions designed to maximize drug effects without exacerbating existing vascular injury remain to be elucidated.