Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide.
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.


RESULTS
MPIO (4.5 microm) 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)-alpha 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.
McAteer
Martina A
MA
Department of Cardiovascular Medicine, University of Oxford, Oxford, OX3 9DU, United Kingdom.
Schneider
Jurgen E
JE
Ali
Ziad A
ZA
Warrick
Nicholas
N
Bursill
Christina A
CA
von zur Muhlen
Constantin
C
Greaves
David R
DR
Neubauer
Stefan
S
Channon
Keith M
KM
Choudhury
Robin P
RP
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001161:Arteriosclerosis / Q000175:diagnosis* / Q000503:physiopathology; D002448:Cell Adhesion / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D005290:Ferric Compounds; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D018345:Mice, Knockout; D019007:P-Selectin / Q000502:physiology*; D010316:Particle Size; D012680:Sensitivity and Specificity; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
D001057:Apolipoproteins E; D005290:Ferric Compounds; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; C000499:ferric oxide