Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 26, Issue 9, Pages 2103-2109Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.ATV.0000235724.11299.76
Keywords
magnetic resonance imaging; atherosclerosis; molecular imaging; angiogenesis; nanoparticles; fumagillin
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Funding
- NCI NIH HHS [N01-CO-37007] Funding Source: Medline
- NHLBI NIH HHS [HL-78631, HL-73646] Funding Source: Medline
- NIBIB NIH HHS [EB-01704] Funding Source: Medline
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Objective - Angiogenic expansion of the vasa vasorum is a well-known feature of progressive atherosclerosis, suggesting that antiangiogenic therapies may stabilize or regress plaques. alpha(v)beta(3) 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 alpha(v)beta(3) 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 mu g/kg or 30 mu g/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 alpha(v)beta(3)-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.
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