Drug-eluting polymer-coated coronary stents : an in vitro and in vivo evaluation of antirestenotic potential

Percutaneous intervention (PCI) is complicated by restenosis, stent thrombosis and delayed endothelial recovery at the PCI site. One approach to reduce these complications is to deliver potent agents directly to the PCI site. This local drug delivery can be achieved by absorbing drugs into a polymer coating applied to the stent itself. In this thesis three such agents have been examined as potential anti-restenosis agents. Vascular Endothelial Growth Factor (VEGF) has been shown to accelerate the recovery of endothelium over a stent, reducing intimal hyperplasia and thrombosis. It has not previously been delivered bound onto the stent itself. VEGF-eluting stents were tested in vitro and in a rabbit model. Paclitaxel-eluting stents prevent restenosis in animal and clinical studies. This effectiveness was use to develop a new organ culture model of in-stent restenosis. Abciximab, which blocks the smooth muscle cell (SMC) vitronectin integrin, was tested in vitro as a stent-based therapy. Results: 21.7μg of VEGF was absorbed. This was released with a biexponential release curve with 20% remaining at 9 days. In arterial tissue, 11% of the VEGF was detectable in the tissue at 24hr. 125μg of paclitaxel and 2.85μg of Abciximab were absorbed after very short absorption times, with biexponential release kinetics. VEGF-eluting stents stimulated endothelial cell growth by 11% over 5 days, with effects that were sustained beyond the initial rapid VEGF release. Organ culture showed that the SMC response to stent implantation could be reproduced in vitro and that the effects of drug-eluting stents could be measured using this new model. Paclitaxel-eluting stents reduced SMC proliferation. The animal studies showed a trend (p=0.07) towards reduced platelet deposition early after PCI, with reduced thrombus formation at 7 days (12.5mg in VEGF stents vs. 0mg in controls). No benefit of VEGF stents was seen on the re-endothelialisation process or on intimal hyperplasia.