Novel peri-vascular drug delivery for the treatment of neointimal hyperplasia associated with PTFE dialysis graft failure.

摘要

Intimal hyperplasia (IH), that leads to hemodialysis access dysfunction, is a major problem affecting patients undergoing renal dialysis. This work aimed at developing a novel approach that entails peri-vascular delivery of cytotoxic agents such as paclitaxel for the inhibition of IH. We formulated a polymeric delivery system for use as a peri-vascular wrap around the graft-vein junction. The formulation was rigorously optimized with respect to its mechanical strength and in vitro drug release kinetics. The optimized formulation used ethylene-vinyl acetate polymer and PEG4000 as the channeling agent (15%) with paclitaxel loading of 5%. This formulation exhibited a biphasic release profile (initial burst followed by sustained release for >28 days), which is coincident with the time course of intimal thickening. The formulation was then tested for paclitaxel cytotoxicity against a panel of cells that are known to be involved in IH such as smooth muscle and endothelial cells MTT cell viability assay. The formulation retained paclitaxel cytotoxicity against all cell types investigated. Pharmacodynamic assessment entailed a comparative evaluation of IH employing a validated pig model (Yorkshire pigs). Dialysis grafts were implanted between the femoral artery and vein.{09}One side received drug-loaded peri-vascular wrap, while the contra-lateral side received drug-free wraps (controls) for 23--37 days. Histomorphometric analysis of sections from control versus drug-treated tissues indicated complete inhibition of IH on the treatment side, while the control side exhibited ∼56% neointimal blockage. Pharmacokinetic studies indicated that paclitaxel was not detectable in plasma samples (limit of quantitation, 50 nM). Taken together, our studies propose an exciting novel drug delivery approach for the treatment of vascular stenosis. They provide strong scientific bases for further pre-clinical and clinical evaluation for prevention of dialysis grafts failure and other vascular abnormalities where IH is the underlying pathology.