Intramural Delivery of Rapamycin With α v β 3 -Targeted Paramagnetic Nanoparticles Inhibits Stenosis After Balloon Injury

Abstract

Background— Drug eluting stents prevent vascular restenosis but can delay endothelial healing. A rabbit femoral artery model of stenosis formation after vascular injury was used to study the effect of intramural delivery of α v β 3 -integrin-targeted rapamycin nanoparticles on vascular stenosis and endothelial healing responses. Methods and Results— Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were locally treated with either (1) α v β 3 -targeted rapamycin nanoparticles, (2) α v β 3 -targeted nanoparticles without rapamycin, (3) nontargeted rapamycin nanoparticles, or (4) saline. Intramural binding of integrin-targeted paramagnetic nanoparticles was confirmed with MR molecular imaging (1.5 T). MR angiograms were indistinguishable between targeted and control arteries at baseline, but 2 weeks later they showed qualitatively less luminal plaque in the targeted rapamycin treated segments compared with contralateral control vessels. In a first cohort of 19 animals (38 vessel segments), microscopic morphometric analysis of the rapamycin-treated segments revealed a 52% decrease in the neointima/media ratio ( P <0.05) compared to control. No differences ( P >0.05) were observed among balloon injured vessel segments treated with α v β 3 -targeted nanoparticles without rapamycin, nontargeted nanoparticles with rapamycin, or saline. In a second cohort of 29 animals, endothelial healing followed a parallel pattern over 4 weeks in the vessels treated with α v β 3 -targeted rapamycin nanoparticles and the 3 control groups. Conclusions— Local intramural delivery of α v β 3 -targeted rapamycin nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury.