Endothelial alpha(v)beta3 integrin-targeted fumagillin nanoparticles inhibit angiogenesis in atherosclerosis.
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)beta3 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.


RESULTS
Expression of alpha(v)beta3 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 microg/kg or 30 microg/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)beta3-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.
Winter
Patrick M
PM
Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Neubauer
Anne M
AM
Caruthers
Shelton D
SD
Harris
Thomas D
TD
Robertson
J David
JD
Williams
Todd A
TA
Schmieder
Anne H
AH
Hu
Grace
G
Allen
John S
JS
Lacy
Elizabeth K
EK
Zhang
Huiying
H
Wickline
Samuel A
SA
Lanza
Gregory M
GM
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000473:pathology; D050197:Atherosclerosis / Q000150:complications / Q000175:diagnosis / Q000378:metabolism*; D003510:Cyclohexanes; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage* / Q000494:pharmacology; D006949:Hyperlipidemias / Q000097:blood; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D049329:Nanostructures; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control*; D011817:Rabbits; D012717:Sesquiterpenes
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D039302:Integrin alphaVbeta3; D012717:Sesquiterpenes; C026211:fumagillin