OBJECTIVE: Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. METHODS AND RESULTS: In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P<0.05), but reduced by 30 weeks (P<0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R=0.53; P<0.01). Near-infrared fluorescently labeled PV-MPIO were shown, by flow cytometry, to bind only activated endothelial cells and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis-spared regions. CONCLUSIONS: This high-affinity leukocyte-mimetic magnetic resonance imaging agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous magnetic resonance contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative magnetic resonance imaging of inflammatory disease activity.

Original publication

DOI

10.1161/ATVBAHA.111.241844

Type

Journal article

Journal

Arterioscler Thromb Vasc Biol

Publication Date

06/2012

Volume

32

Pages

1427 - 1435

Keywords

Animals, Antibodies, Antibody Affinity, Aorta, Aortic Diseases, Apolipoproteins E, Atherosclerosis, Binding Sites, Antibody, Biomimetic Materials, Contrast Media, Disease Models, Animal, Disease Progression, Endothelium, Vascular, Female, Ferric Compounds, Flow Cytometry, Humans, Immunohistochemistry, Leukocytes, Ligands, Macrophages, Magnetic Resonance Imaging, Mice, Mice, Inbred C57BL, Mice, Knockout, P-Selectin, Particle Size, Spectroscopy, Near-Infrared, Time Factors, Vascular Cell Adhesion Molecule-1