Restenosis following angioplasty remains a major factor limiting the long-term success of this form of therapy. Many of the failures of pharmacological therapy for restenosis in animal models are related to systemic intolerance or difficulty in providing controlled administration of drugs for adequate periods of time.Therefore, our studies have been directed towards the development of local, sustained-release delivery vehicles and the use of adenoviral-mediated gene transfer. We have previously reported that taxol, significantly inhibited intimal thickening following balloon injury to the rat carotid artery when given systemically intraperitoneally. In order to locally deliver taxol and other drugs at high concentrations locally and limit potential systemic side effects, we have developed sustained-release biodegradable microcapsules to encapsulate bioactive compounds. Applying these microcapsules loaded with taxol to the adventitial side of the rat carotid artery following balloon injury resulted in a dose-dependent inhibition of neointimal regrowth (restenosis) without a host inflammatory response. In addition to taxol, peptides that inhibit matrix metalloproteinase (MMP)activation are also being tested. We have also began to develop a technique for intravascular drug delivery using polymeric films coated onto intraluminal stents. Preliminary results reveal that tantalum and stainless steel stents provide a satisfactory adhesive surface for drug-containing polymeric films.Using the pig coronary artery model of restenosis, future studies will determine whether polymeric coated stents impregnated with taxol or the MMPI provide a useful mechanism for the prevention of restenosis. Intraluminal adenoviral-mediated gene transfer has become an attractice alternative to achieve localized and controlled modulation of the vessel wall following vascular injury. In order to achieve targeted expression of genetic material in the pig coronary artery, we conducted experiments usig a new flow-through catheter, the Dispatch catheter (Boston Scientific, Inc.). Using the reporter gene LacZ and this delivery system, we were unable to achieve efficient localized or reproducible transfection. Additional studies are planned to evaluate other catheter systems and techniques for intra-coronary gene delivery.
