Endothelial ανβ3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis

Patrick M. Winter, Anne M. Neubauer, Shelton D. Caruthers, Thomas D. Harris, J. David Robertson, Todd A. Williams, Anne H. Schmieder, Grace Hu, John S. Allen, Elizabeth K. Lacy, Huiying Zhang, Samuel A. Wickline, Gregory M. Lanza

Research output: Contribution to journalArticlepeer-review

334 Scopus citations

Abstract

OBJECTIVE - Angiogenic expansion of the vasa vasorum is a well-known feature of progressive atherosclerosis, suggesting that antiangiogenic therapies may stabilize or regress plaques. ανβ3 Integrin-targeted paramagnetic nanoparticles were prepared for noninvasive assessment of angiogenesis in early atherosclerosis, for site-specific delivery of antiangiogenic drug, and for quantitative follow-up of response. METHODS AND RESULTS - Expression of ανβ3 integrin by vasa vasorum was imaged at 1.5 T in cholesterol-fed rabbit aortas using integrin-targeted paramagnetic nanoparticles that incorporated fumagillin at 0 μg/kg or 30 μg/kg. Both formulations produced similar MRI signal enhancement (16.7%±1.1%) when integrated across all aortic slices from the renal arteries to the diaphragm. Seven days after this single treatment, integrin-targeted paramagnetic nanoparticles were readministered and showed decreased MRI enhancement among fumagillin-treated rabbits (2.9%±1.6%) but not in untreated rabbits (18.1%±2.1%). In a third group of rabbits, nontargeted fumagillin nanoparticles did not alter vascular ανβ3-integrin expression (12.4%±0.9%; P>0.05) versus the no-drug control. In a second study focused on microscopic changes, fewer microvessels in the fumagillin-treated rabbit aorta were counted compared with control rabbits. CONCLUSIONS - This study illustrates the potential of combined molecular imaging and drug delivery with targeted nanoparticles to noninvasively define atherosclerotic burden, to deliver effective targeted drug at a fraction of previous levels, and to quantify local response to treatment.

Original languageEnglish
Pages (from-to)2103-2109
Number of pages7
JournalArteriosclerosis, thrombosis, and vascular biology
Volume26
Issue number9
DOIs
StatePublished - Sep 2006

Keywords

  • Angiogenesis
  • Atherosclerosis
  • Fumagillin
  • Magnetic resonance imaging
  • Molecular imaging
  • Nanoparticles

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