Neointimal hyperplasia is a frequent cause of stenosis in blood vessels and is commonly observed in post-angioplasty coronary arteries and hemodialysis vascular accesses. In native arteriovenous (AV) fistulae and polytetrafluoroethylene (PTFE) grafts for hemodialysis, the stenosis is usually focal and occurs at the AV or graft-venous anastomosis. Effective strategies for the prevention of stenosis are lacking. We hypothesize that local delivery of anti-proliferative drugs and anti-growth factor antibodies using a novel drug delivery system, ReGel, will inhibit neointimal hyperplasia associated with native AV fistulae and PTFE grafts. ReGel is an injectable, thermosensitive copolymer designed for local, sustained-delivery of drugs. This is a multidisciplinary approach to address the following specific aims: (1) To examine the efficacy of two anti-proliferative drugs (dipyridamole or paclitaxel) and anti-platelet derived growth factor (PDGF) antibodies alone or in combinations in the inhibition of growth of human or canine vascular smooth muscle cells. These in vitro studies will set the stage for animal studies in this proposal and potential clinical trials in the future. (2) To study the release kinetics of the anti-proliferative drugs and anti-PDGF antibodies from ReGel in vitro and their transport kinetics across explanted native AV fistulae and PTFE grafts. The transport characteristics of the drugs and antibodies in ReGel applied to the perivascular area of the native AV fistula and PTFE graft around the venous anastomosis will then be evaluated in whole dog experiments. Comparisons of mathematical model predictions with results from these experiments will help optimize the therapeutic dose of drugs and antibodies and conditions for delivery by ReGel in vivo. (3) To examine the efficacy of the anti-proliferative drugs and anti-PDGF antibodies delivered by ReGel in inhibiting neointimal hyperplasia in dog models of native AV fistula and PTFE graft. Successful development of this technique will provide a novel approach of local drug delivery to prevent neointimal hyperplasia and stenosis in blood vessels. Furthermore, the results will provide the basis for local delivery of drugs and proteins of interest to a variety of tissues.
Showing the most recent 10 out of 37 publications
