Intramural delivery of rapamycin with alphavbeta3-targeted paramagnetic nanoparticles inhibits stenosis after balloon injury.
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 alpha(v)beta(3)-integrin-targeted rapamycin nanoparticles on vascular stenosis and endothelial healing responses.


RESULTS
Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were locally treated with either (1) alpha(v)beta(3)-targeted rapamycin nanoparticles, (2) alpha(v)beta(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 alpha(v)beta(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 alpha(v)beta(3)-targeted rapamycin nanoparticles and the 3 control groups.


CONCLUSIONS
Local intramural delivery of alpha(v)beta(3)-targeted rapamycin nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury.
Cyrus
Tillmann
T
Division of Cardiology, Washington University School of Medicine, Saint Louis, Mo. 63108, USA. tcyrus@im.wustl.edu
Zhang
Huiying
H
Allen
John S
JS
Williams
Todd A
TA
Hu
Grace
G
Caruthers
Shelton D
SD
Wickline
Samuel A
SA
Lanza
Gregory M
GM
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000494:pharmacology; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D054855:Drug-Eluting Stents; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005263:Femoral Artery / Q000187:drug effects / Q000473:pathology; D039302:Integrin alphaVbeta3 / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging; D008297:Male; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D039302:Integrin alphaVbeta3; D020123:Sirolimus