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

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. 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.

METHODS AND 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.

• Authors: 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
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 26 Issue 9 Pg. 2103-9 (Sep 2006) ISSN: 1524-4636 [Electronic] United States
• PMID: 16825592 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Cyclohexanes
• Fatty Acids, Unsaturated
• Integrin alphaVbeta3
• Sesquiterpenes
• fumagillin

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Animals
• Aorta, Abdominal (pathology)
• Atherosclerosis (complications, diagnosis, metabolism)
• Cyclohexanes
• Drug Delivery Systems
• Endothelium, Vascular (metabolism)
• Fatty Acids, Unsaturated (administration & dosage, pharmacology)
• Hyperlipidemias (blood)
• Integrin alphaVbeta3 (metabolism)
• Magnetic Resonance Imaging
• Nanostructures
• Neovascularization, Pathologic (etiology, prevention & control)
• Rabbits
• Sesquiterpenes