on September 25, 2006
Published online before print September 25, 2006, doi: 10.1161/CIRCULATIONAHA.106.646380
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Submitted on February 2, 2006
From the Center for Molecular Imaging Research (M.N., F.A.J., K.A.K., D.E.S., E.A., R.W.) and Cardiology Division, Department of Medicine (F.A.J., D.E.S.), Massachusetts General Hospital; Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital (P.L.); and Donald W. Reynolds Cardiovascular Clinical Research Center, Harvard Medical School (M.N., F.A.J., K.A.K., E.A., P.L., R.W.), Boston, Mass. * To whom correspondence should be addressed. E-mail: fjaffer{at}partners.org.
Background--Noninvasive imaging of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) may identify early stages of inflammation in atherosclerosis. We hypothesized that a novel, second-generation VCAM-1-targeted agent with enhanced affinity had sufficient sensitivity to enable real-time detection of VCAM-1 expression in experimental atherosclerosis in vivo, to quantify pharmacotherapy-induced reductions in VCAM-1 expression, and to identify activated cells in human plaques. Methods and Results--In vivo phage display in apolipoprotein E-deficient mice identified a linear peptide affinity ligand, VHPKQHR, homologous to very late antigen-4, a known ligand for VCAM-1. This peptide was developed into a multivalent agent detectable by MRI and optical imaging (denoted VINP-28 for VCAM-1 internalizing nanoparticle 28, with 20 times higher affinity than previously reported for VNP). In vitro, VINP-28 targeted all cell types expressing VCAM-1. In vivo, MRI and optical imaging in apolipoprotein E-deficient mice (n=28) after injection with VINP-28 or saline revealed signal enhancement in the aortic root of mice receiving VINP-28 (P<0.05). VINP-28 colocalized with endothelial cells and other VCAM-1-expressing cells, eg, macrophages, and was spatially distinct compared with untargeted control nanoparticles. Atheromata of atorvastatin-treated mice showed reduced VINP-28 deposition and VCAM-1 expression. VINP-28 enhanced early lesions in juvenile mice and resected human carotid artery plaques. Conclusions--VINP-28 allows noninvasive imaging of VCAM-1-expressing endothelial cells and macrophages in atherosclerosis and spatial monitoring of anti-VCAM-1 pharmacotherapy in vivo and identifies inflammatory cells in human atheromata. This clinically translatable agent could noninvasively detect inflammation in early, subclinical atherosclerosis.
Revised on June 16, 2006
Accepted on July 31, 2006
Noninvasive Vascular Cell Adhesion Molecule-1 Imaging Identifies Inflammatory Activation of Cells in Atherosclerosis
Matthias Nahrendorf MD,
Key words: atherosclerosis • cell adhesion molecules • imaging • inflammation • magnetic resonance imaging
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