title: Scavenger receptor-AI-targeted iron oxide nanoparticles for in vivo MRI detection of atherosclerotic lesions.
abstract: OBJECTIVE
  In search of molecular imaging modalities for specific detection of inflammatory atherosclerotic plaques, we explored the potential of targeting scavenger receptor-AI (SR-AI), which is highly expressed by lesional macrophages and linked to effective internalization machinery.
  
  
  RESULTS
  Ultrasmall superparamagnetic iron oxide particles were conjugated to a peptidic SR-AI ligand (0.371 mol Fe/L and 0.018 mol PP1/L). In vitro incubation of human or murine macrophages with SR-AI-targeted USPIO led to significantly higher iron uptake in vitro than with nontargeted USPIO, as judged by quantitative atomic absorption spectroscopy and Perl's staining. Incremental uptake was strictly mediated by SRs. SR-AI-targeted USPIO displayed accelerated plasma decay and a 3.5-fold increase (P=0.01) in atherosclerotic plaque accumulation on intravenous injection into apolipoprotein E-deficient mice compared with nontargeted USPIO. In addition, atherosclerotic humanized LDLr(-/-) chimeras with leukocyte expression of human SR-AI showed a significant improvement in contrast-to-noise ratio (2.7-fold; P=0.003) in the atherosclerotic aortic arch plaques 24 hours after injection of SR-AI-targeted USPIO compared with chimeras with leukocyte SR-AI deficiency.
  
  
  CONCLUSIONS
  Collectively, our data provide several lines of evidence that SR-AI-targeted molecular imaging of USPIO-based contrast agents holds great promise for in situ detection of inflammatory plaques in manifest atherosclerosis.
authors.affiliation: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, The Netherlands. l f.segers@maastrichtuniversity.nl
authors.forename: Filip M E
authors.initials: FM
authors.lastname: Segers
authors.forename: Brigit
authors.initials: B
authors.lastname: den Adel
authors.forename: Ilze
authors.initials: I
authors.lastname: Bot
authors.forename: Linda M
authors.initials: LM
authors.lastname: van der Graaf
authors.forename: Eric P
authors.initials: EP
authors.lastname: van der Veer
authors.forename: Walter
authors.initials: W
authors.lastname: Gonzalez
authors.forename: Isabelle
authors.initials: I
authors.lastname: Raynal
authors.forename: Menno
authors.initials: M
authors.lastname: de Winther
authors.forename: Will K
authors.initials: WK
authors.lastname: Wodzig
authors.forename: Robert E
authors.initials: RE
authors.lastname: Poelmann
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weerd
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D002478:Cells, Cultured; D003911:Dextrans / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D018345:Mice, Knockout; D053758:Nanoparticles; D058226:Plaque, Atherosclerotic / Q000378:metabolism* / Q000473:pathology*; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013054:Spectrophotometry, Atomic / Q000379:methods
chemical_list: D001057:Apolipoproteins E; D003911:Dextrans; C495139:MSR1 protein, human; D058185:Magnetite Nanoparticles; C495140:Msr1 protein, mouse; D051117:Scavenger Receptors, Class A; C097921:ferumoxtran-10
keywords: atherosclerosis; macrophages; magnetic resonance imaging; molecular imaging; receptors, scavenger; ultrasmall superparamagnetic iron oxide