Currently available interventional therapeutic options for the treatment of obstructive coronary artery disease comprise balloon-facilitated dilatation, followed by implantation of bare metal (BMS) or drug-eluting (DES) stents. Although these have led to a significant decrease of mortality following myocardial infarction, their long-term clinical outcomes may be limited. While BMS inherently lack sufficient efficacy to suppress neointimal growth, DES have impressively reduced this shortcoming. In consequence, in-stent restenosis could dramatically be reduced with the use of DES. However, DES are hampered by a prolonged need for potent anti-platelet therapy due to a substantial deficiency in endothelialization and biocompatibility. Therefore patients undergoing BMS or DES implantation are often in need of further revascularizations or, respectively, have to maintain long-term anti-platelet therapy, which poses them at significant bleeding risk.
In order to circumvent the limitations of current stent technologies, the aim of the current project is to render the stent surface more biocompatible. This will be achieved by influencing the migration and proliferation of vascular smooth muscle cells (VSMCs) to selectively inhibit vessel re-narrowing, and simultaneously by enhancing endothelial cell (EC) recovery of the luminal stent surface. Integrins, as extra and intracellular receptor proteins, are of great importance in cell-cell and cell-extracellular matrix interactions and are distinguishingly expressed on VSMCs and ECs (e.g avb3 and a5b1). Using RGD-peptides and peptidomimetics with high affinity and selectivity towards specific integrin receptor subtypes, we will be able to selectively target these cells and influence independently in their migrative and proliferative character. As shown schematically below (see Figure) our goal is to construct a biocompatible stent which combines i) the abluminal release of selective a5b1 ligands to suppress neointimal growth; and ii) the luminal binding of ligands selective for avb3 to the stent surface for enhanced re-endothelialization.