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

Applying local drug delivery techniques in treating restenosis with an tiproliferative agents may prove useful in enhancing drug efficacy whi le minimizing inherent systemic toxicity. Using direct intramural deli very of drug-loaded nanoparticles (U-86NP) composed of the biodegradab le 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 th e 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 modi fication, and suspension concentration that maximized U-86NP retention in balloon-injured arterial segments. A chronic efficacy study implem enting these delivery conditions was then performed in domestic feeder pigs. Site-specific delivery of U-86NP significantly reduced neointim al hyperplasia in severely balloon-injured porcine coronary arteries b ut also increased the incidence of medial dissection at the treated si te. Delivery conditions designed to maximize drug effects without exac erbating existing vascular injury remain to be elucidated.