Noninvasive vascular cell adhesion molecule-1 imaging identifies inflammatory activation of cells in atherosclerosis.
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.


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.
Nahrendorf
Matthias
M
Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, USA.
Jaffer
Farouc A
FA
Kelly
Kimberly A
KA
Sosnovik
David E
DE
Aikawa
Elena
E
Libby
Peter
P
Weissleder
Ralph
R
D000595:Amino Acid Sequence; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology*; D003952:Diagnostic Imaging / Q000379:methods; D015536:Down-Regulation / Q000187:drug effects; D016903:Drug Monitoring / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000175:diagnosis*; D008024:Ligands; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis* / Q000187:drug effects
D001057:Apolipoproteins E; D008024:Ligands; D010455:Peptides; D019010:Vascular Cell Adhesion Molecule-1