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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:77.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Magnetic Resonance Imaging of Endothelial Adhesion Molecules in Mouse Atherosclerosis Using Dual-Targeted Microparticles of Iron Oxide

Martina A. McAteer; Jurgen E. Schneider; Ziad A. Ali; Nicholas Warrick; Christina A. Bursill; Constantin von zur Muhlen; David R. Greaves; Stefan Neubauer; Keith M. Channon; Robin P. Choudhury

From the Department of Cardiovascular Medicine (M.A.M., J.E.S., Z.A.A., N.W., C.A.B., C.v.z.M., S.N., K.M.C., R.P.C.) and Sir William Dunn School of Pathology (D.R.G.), Oxford, University of Oxford, United Kingdom.

Correspondence to Dr Robin Choudhury, Department of Cardiovascular Medicine, Level 5, John Radcliffe Hospital, Oxford, OX3 9DU, United Kingdom. E-mail robin.choudhury{at}cardiov.ox.ac.uk

Abstract

Objective— Microparticles of iron oxide (MPIO) distort magnetic field creating marked contrast effects far exceeding their physical size. We hypothesized that antibody-conjugated MPIO would enable magnetic resonance imaging (MRI) of endothelial cell adhesion molecules in mouse atherosclerosis.

Methods and Results— MPIO (4.5 µm) were conjugated to monoclonal antibodies against vascular cell adhesion molecule-1 (VCAM–MPIO) or P-selectin (P-selectin–MPIO). In vitro, VCAM–MPIO bound, in dose-dependent manner, to tumor necrosis factor (TNF)- stimulated sEND-1 endothelial cells, as quantified by light microscopy (R²=0.94, P=0.03) and by MRI (R²=0.98, P=0.01). VCAM–MPIO binding was blocked by preincubation with soluble VCAM-1. To mimic leukocyte binding, MPIO targeting both VCAM-1 and P-selectin were administered in apolipoprotein E^–/– mice. By light microscopy, dual-targeted MPIO binding to endothelium overlying aortic root atherosclerosis was 5- to 7-fold more than P-selectin–MPIO (P<0.05) or VCAM–MPIO (P<0.01) alone. Dual-targeted MPIO, injected intravenously in vivo bound aortic root endothelium and were quantifiable by MRI ex vivo (3.5-fold increase versus control; P<0.01). MPIO were well-tolerated in vivo, with sequestration in the spleen after 24 hours.

Conclusions— Dual-ligand MPIO bound to endothelium over atherosclerosis in vivo, under flow conditions. MPIO may provide a functional MRI probe for detecting endothelial-specific markers in a range of vascular pathologies.

Microparticles of iron oxide (MPIO) were conjugated with monoclonal antibodies targeting VCAM-1 and P-selectin. After in vivo intravenous injection, dual-targeted MPIO binding to aortic root plaque endothelium in apolipoprotein E knockout mice was detected by high-resolution ex vivo MRI.

Key Words: microparticles of iron oxide • atherosclerosis • magnetic resonance imaging • molecular imaging

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