title: A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Level 6 West Wing, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom.
authors.forename: Martina A
authors.initials: MA
authors.lastname: McAteer
authors.forename: Kulveer
authors.initials: K
authors.lastname: Mankia
authors.forename: Neil
authors.initials: N
authors.lastname: Ruparelia
authors.forename: Andrew
authors.initials: A
authors.lastname: Jefferson
authors.forename: Hannah B
authors.initials: HB
authors.lastname: Nugent
authors.forename: Lee-Anne
authors.initials: LA
authors.lastname: Stork
authors.forename: Keith M
authors.initials: KM
authors.lastname: Channon
authors.forename: Jurgen E
authors.initials: JE
authors.lastname: Schneider
authors.forename: Robin P
authors.initials: RP
authors.lastname: Choudhury
mesh_terms: D000818:Animals; D000906:Antibodies; D000915:Antibody Affinity; D001011:Aorta / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D001018:Aortic Diseases / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001666:Binding Sites, Antibody; D040761:Biomimetic Materials; D003287:Contrast Media / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005290:Ferric Compounds; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008024:Ligands; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000276:immunology / Q000378:metabolism; D010316:Particle Size; D019265:Spectroscopy, Near-Infrared; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D001057:Apolipoproteins E; D003287:Contrast Media; D005290:Ferric Compounds; D008024:Ligands; D019007:P-Selectin; C546937:SELP protein, human; D019010:Vascular Cell Adhesion Molecule-1; C000499:ferric oxide