Author + information
- Received March 23, 2008
- Revision received May 19, 2008
- Accepted June 16, 2008
- Published online September 1, 2008.
- Patrick M. Winter, PhD⁎,
- Shelton D. Caruthers, PhD⁎,†,
- Huiying Zhang, MD⁎,
- Todd A. Williams, RT, MR⁎,
- Samuel A. Wickline, MD, FACC⁎ and
- Gregory M. Lanza, MD, PhD, FACC⁎,⁎ ()
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
Objectives Studies were performed to develop a prolonged antiangiogenesis therapy regimen based on theranostic ανβ3-targeted nanoparticles.
Background Antiangiogenesis therapy may normalize atherosclerotic plaque vasculature and promote plaque stabilization. ανβ3-targeted paramagnetic nanoparticles can quantify atherosclerotic angiogenesis and incorporate fumagillin to elicit acute antiangiogenic effects.
Methods In the first experiment, hyperlipidemic rabbits received ανβ3-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 ανβ3-targeted paramagnetic nanoparticles. In a second 8-week study, atherosclerotic rabbits received atorvastatin (0 or 44 mg/kg diet) alone or with ανβ3-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 ανβ3-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 ανβ3-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 ανβ3-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 ανβ3-targeted nanoparticles were constrained to the vasculature of the aortic adventia.
Conclusions The CMR molecular imaging with ανβ3-targeted paramagnetic nanoparticles demonstrated that the acute antiangiogenic effects of ανβ3-targeted fumagillin nanoparticles could be prolonged when combined with atorvastatin, representing a potential strategy to evaluate antiangiogenic treatment and plaque stability.
Supported in part by the National Cancer Institute, National Heart Lung and Blood Institute, and the National Institute for Biomedical Imaging and Bioengineering (HL-78631, HL-73646, N01-CO-37007, N01-CO-27031-16, CA-119342, and EB-01704) and by Philips Healthcare and Philips Research. Dr. Winter is a consultant to Kereos (St. Louis, Missouri). Dr. Caruthers is an employee of Philips Medical Systems (Andover, Massachusetts). Dr. Wickline receives equipment support from Philips Healthcare (Andover, Massachusetts). Drs. Wickline and Lanza are founders and stockholders of Kereos.
- Received March 23, 2008.
- Revision received May 19, 2008.
- Accepted June 16, 2008.
- American College of Cardiology Foundation