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Antiangiogenic Synergism of Integrin-Targeted Fumagillin Nanoparticles and Atorvastatin in Atherosclerosis

Patrick M. Winter, PhD^_*, Shelton D. Caruthers, PhD^_*,, Huiying Zhang, MD^_*, Todd A. Williams, RT, MR^_*, Samuel A. Wickline, MD, FACC^_*, Gregory M. Lanza, MD, PhD, FACC^_*,_*

^_* Washington University, St. Louis, Missouri
Philips Healthcare, Andover, Massachusetts

^_* Reprint requests and correspondence: Dr. Gregory M. Lanza, Washington University School of Medicine, 4320 Forest Park Avenue, Cortex Building, Suite 101, Campus Box 8125, St. Louis, Missouri 63108 (Email: greg{at}cvu.wustl.edu).

Objectives: Studies were performed to develop a prolonged antiangiogenesis therapy regimen based on theranostic β₃-targeted nanoparticles.

Background: Antiangiogenesis therapy may normalize atherosclerotic plaque vasculature and promote plaque stabilization. β₃-targeted paramagnetic nanoparticles can quantify atherosclerotic angiogenesis and incorporate fumagillin to elicit acute antiangiogenic effects.

Methods: In the first experiment, hyperlipidemic rabbits received β₃-targeted fumagillin nanoparticles (0, 30, or 90 µg/kg) with either a continued high fat diet or conversion to standard chow. The antiangiogenic response was followed for 4 weeks by cardiac magnetic resonance (CMR) molecular imaging with β₃-targeted paramagnetic nanoparticles. In a second 8-week study, atherosclerotic rabbits received atorvastatin (0 or 44 mg/kg diet) alone or with β₃-targeted fumagillin nanoparticles (only week 0 vs. weeks 0 and 4), and angiogenesis was monitored with CMR molecular imaging. Histology was performed to determine the location of bound nanoparticles and to correlate the level of CMR enhancement with the density of angiogenic vessels.

Results: The β₃-targeted fumagillin nanoparticles reduced the neovascular signal by 50% to 75% at 1 week and maintained this effect for 3 weeks regardless of diet and drug dose. In the second study, atherosclerotic rabbits receiving statin alone had no antineovascular benefit over 8 weeks. The β₃-targeted fumagillin nanoparticles decreased aortic angiogenesis for 3 weeks as in study 1, and readministration on week 4 reproduced the 3-week antineovascular response with no carry-over benefit. However, atorvastatin and 2 doses of β₃-targeted fumagillin nanoparticles (0 and 4 weeks) achieved marked and sustainable antiangiogenesis. Microscopic studies corroborated the high correlation between CMR signal and neovessel counts and confirmed that the β₃-targeted nanoparticles were constrained to the vasculature of the aortic adventia.

Conclusions: The CMR molecular imaging with β₃-targeted paramagnetic nanoparticles demonstrated that the acute antiangiogenic effects of β₃-targeted fumagillin nanoparticles could be prolonged when combined with atorvastatin, representing a potential strategy to evaluate antiangiogenic treatment and plaque stability.

Key Words: angiogenesis • molecular imaging • fumagillin • nanoparticle

Abbreviations and Acronyms   AlkP = alkaline phosphatase   ALT = alanine aminotransferase   AST = aspartate aminotransferase   CMR = cardiac magnetic resonance   GGT = gamma glutamyltransferase   MetAP = methionine aminopeptidase

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