title: Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide.
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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, Oxford, OX3 9DU, United Kingdom.
authors.forename: Martina A
authors.initials: MA
authors.lastname: McAteer
authors.forename: Jurgen E
authors.initials: JE
authors.lastname: Schneider
authors.forename: Ziad A
authors.initials: ZA
authors.lastname: Ali
authors.forename: Nicholas
authors.initials: N
authors.lastname: Warrick
authors.forename: Christina A
authors.initials: CA
authors.lastname: Bursill
authors.forename: Constantin
authors.initials: C
authors.lastname: von zur Muhlen
authors.forename: David R
authors.initials: DR
authors.lastname: Greaves
authors.forename: Stefan
authors.initials: S
authors.lastname: Neubauer
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
mesh_terms: 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*
chemical_list: D001057:Apolipoproteins E; D005290:Ferric Compounds; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; C000499:ferric oxide