Development of a Local Perivascular Paclitaxel Delivery System for Hemodialysis Vascular Access Dysfunction: Polymer Preparation and in vitroActivity

Abstract

Hemodialysis vascular access dysfunction (HVAD) is currently a huge clinical problem. The major cause of HVAD is venous stenosis (as a result of venous neointimal hyperplasia) which leads to thrombosis in polytetrafluoroethylene dialysis access grafts and fistulae. Despite the magnitude of the clinical problem there are currently no effective therapeutic interventions for this condition. In an attempt to reduce the morbidity associated with HVAD, we have developed and validated a local perivascular paclitaxel release system for use in a pig model of arteriovenous graft stenosis. Ethylene vinyl acetate polymers with 5% paclitaxel were formulated. The release profile of paclitaxel was then manipulated to maximize its biological impact in the in vivo situation. In vitro experiments were performed to confirm that the paclitaxel released from the polymer was biologically active against cell types that were similar to those present in the in vivo lesion of neointimal hyperplasia. Our results demonstrate that the paclitaxel polymer wraps which we have developed are mechanically stable with a burst release phase followed by a slower continuous release phase. The paclitaxel released from these polymeric wraps retains its physicochemical and biological properties and is able to inhibit the proliferation of smooth muscle cells, endothelial cells and fibroblasts in vitro. We believe that these paclitaxel-loaded polymeric wraps could be ideally suited for perivascular drug delivery in the context of dialysis access grafts and fistulae.