ABSTRACT
The long-term clinical efficacy of intracoronary stenting is limited by restenosis, which occurs in 15 to 30% of patients.1,2 In-stent restenosis is due solely to neointimal hyperplasia.3-5 Stent-induced mechanical arterial injury and a foreign body response to the prosthesis incites acute and chronic inflammation in the vessel wall with elaboration of cytokines and growth factors that induce multiple signaling pathways to activate SMC migration and proliferation.3-5 Drug eluting stents have been proposed as a means of preventing stent thrombosis and restenosis.6,7 Immobilized heparin surface coating of stents appears to reduce stent thrombogenicity favorably.7 The efficacy of drug eluting stents for the prevention of restenosis has been limited by issues of polymer biocompatibility, suitability of pharmacological agents, suboptimal in vivo pharmacokinetic properties and local drug toxicity.6,8
Experimental data suggest that inhibition of cell cycle progression with prolonged parenteral sirolimus (SRL) may be an effective strategy to prevent restenosis.8-10 SRL is a potent immunosuppressive agent with anti-inflammatory and antiproliferative effects. Gallo et al. recently demonstrated a reduction in postangioplasty restenosis with prolonged systemic SRL therapy in a porcine coronary model of restenosis.10 SRL is a hydrophobic drug that has low solubility in aqueous solutions.11,12 Because of its lipophilicity, the drug passes easily through cell membranes, enabling intramural distribution and prolonged arterial tissue retention.12 Further, cellular uptake is enhanced by binding to the cytosolic receptor, FKBP 12, which also may enhance chronic tissue retention of SRL. Thus, the known biologic effects and pharmacokinetic properties of SRL suggest that the agent is an ideal candidate for a stent-based delivery to prevent restenosis.
