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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:820.)
© 2008 American Heart Association, Inc.

Integrated Physiology/Experimental Medicine

Intramural Delivery of Rapamycin With _vβ₃-Targeted Paramagnetic Nanoparticles Inhibits Stenosis After Balloon Injury

Tillmann Cyrus; Huiying Zhang; John S. Allen; Todd A. Williams; Grace Hu; Shelton D. Caruthers; Samuel A. Wickline; Gregory M. Lanza

From the Division of Cardiology (T.C., H.Z., J.S.A., T.A.W., G.H., S.A.W., G.M.L.), Washington University School of Medicine, Saint Louis, Mo; and Philips Medical Systems (S.D.C.), Andover, Mass.

Correspondence to Tillmann Cyrus, MB, MD, Washington University School of Medicine, 4320 Forest Park Avenue, Suite 101, Campus Box 8215, Saint Louis, MO 63108. E-mail tcyrus{at}im.wustl.edu

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 _vβ₃-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) _vβ₃-targeted rapamycin nanoparticles, (2) _vβ₃-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 _vβ₃-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 _vβ₃-targeted rapamycin nanoparticles and the 3 control groups.

Conclusions— Local intramural delivery of _vβ₃-targeted rapamycin nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury.

Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were treated locally with either: (1) _vβ₃-targeted rapamycin nanoparticles, (2) _vβ₃-targeted nanoparticles without rapamycin, (3) nontargeted rapamycin nanoparticles, or (4) saline. Intramural delivery of _vβ₃-targeted rapamycin nanoparticles inhibited stenosis at 2 weeks without delaying endothelial healing following balloon injury over 4 weeks.

Key Words: nanoparticles • MRI • restenosis • rapamycin • drug delivery