Restenosis following percutaneous transluminal coronary angioplasty (PTCA) remains a major factor limiting the long-term success of this therapy for symptomatic coronary artery disease (CAD). Restenosis is also a late complication of arterio-venous shunt formation in hemodialysis patients. Failures of pharmacological therapy for restenosis are related to systemic intolerance or the difficulty of providing controlled administration of drugs over time. Interest has therefore shifted away from systemic drug therapy to local administration at the site of arterial injury following PTCA. We have shown that taxol, a potent microtubule stabilizing agent, significantly inhibited intimal thickening following balloon injury to the rat carotid artery when administered systemically. In attempt to establish a local delivery system, biodegradable microspheres and films were prepared with taxol or Galardin (matrix metalloproteinase inhibitor, MMPI) and applied to the advential surface of the injured carotid artery. Results showed significant (35-100%) site-specific inhibition of neointimal growth by both drugs with minimal inflammatory response. Advential drug delivery is not feasible in human coronary arteries. We have begun to develop a technique for intravascular drug delivery using polymeric films coated onto intraluminal stents. Using the technology for preparing microbeads, we coated stents with thin films consisting of gelatin and chondroitin sulfate cross-linked with gluteraldehyde for enhanced stability. We have shown that tantalum and stainless steel stents provide a satisfactory adhesive surface during stent expansion and that biologically active amounts of taxol can be incorporated into these films. Using the pig coronary artery model of restenosis, our preliminary studies suggest that polymer-coated metallic stents incorporating taxol provide a useful approach to inhibiting neointimal hyperplasia following balloon injury.
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NIH ExPorter