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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2103.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Endothelial ß₃ 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

From the Department of Medicine (P.M.W., A.M.N., S.D.C., T.A.W., A.H.S., G.H., J.S.A., E.K.L., H.Z., S.A.W., G.M.L.), Cardiovascular Magnetic Resonance Laboratories, Washington University School of Medicine, St Louis, Mo; Philips Medical Systems (S.D.C.), Cleveland, Ohio; Bristol-Myers Squibb Medical Imaging (T.D.H.), Billerica, Mass; and the University of Missouri Research Reactor (J.D.R.), Columbia.

Correspondence to Patrick M. Winter, PhD, Department of Medicine, Washington University, 660 S Euclid Ave, Campus Box 8086, St Louis, MO 63110. E-mail patrick{at}cvu.wustl.edu; or Gregory M. Lanza, MD, PhD. E-mail greg@cvu.wustl.edu

Objective— Angiogenic expansion of the vasa vasorum is a well-known feature of progressive atherosclerosis, suggesting that antiangiogenic therapies may stabilize or regress plaques. ß₃ 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 ß₃ 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 ß₃-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.

ß₃-Targeted paramagnetic nanoparticles were used to detect early atherosclerosis, to deliver an antiangiogenic drug, and to quantitatively assess neovascular response. This dual molecular imaging drug-delivery agent suggests that nanomedicine may provide an opportunity to intervene in the clinical progression of atherosclerosis, particularly in asymptomatic patients.

Key Words: magnetic resonance imaging • atherosclerosis • molecular imaging • angiogenesis • nanoparticles • fumagillin

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