Intramural delivery of rapamycin with alphavbeta3-targeted paramagnetic nanoparticles inhibits stenosis after balloon injury

Arterioscler Thromb Vasc Biol. 2008 May;28(5):820-6. doi: 10.1161/ATVBAHA.107.156281. Epub 2008 Feb 21.

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 alpha(v)beta(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) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angioplasty, Balloon / adverse effects*
  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacology
  • Constriction, Pathologic / drug therapy
  • Constriction, Pathologic / pathology
  • Constriction, Pathologic / prevention & control*
  • Drug-Eluting Stents
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / pathology
  • Femoral Artery / drug effects
  • Femoral Artery / pathology
  • Integrin alphaVbeta3 / administration & dosage*
  • Magnetic Resonance Imaging
  • Male
  • Nanomedicine / methods
  • Nanoparticles / administration & dosage
  • Nanoparticles / therapeutic use*
  • Rabbits
  • Sirolimus / administration & dosage*
  • Sirolimus / pharmacology

Substances

  • Anti-Bacterial Agents
  • Integrin alphaVbeta3
  • Sirolimus