title: Targeted iron oxide particles for in vivo magnetic resonance detection of atherosclerotic lesions with antibodies directed to oxidation-specific epitopes.
abstract: OBJECTIVE
  The aim of this study was to determine whether iron oxide particles targeted to oxidation-specific epitopes image atherosclerotic lesions.
  
  
  BACKGROUND
  Oxidized low-density lipoprotein plays a major role in atherosclerotic plaque progression and destabilization. Prior studies indicate that gadolinium micelles labeled with oxidation-specific antibodies allow for in vivo detection of vulnerable plaques with magnetic resonance imaging (MRI). However, issues related to biotransformation/retention of gadolinium might limit clinical translation. Iron oxides are recognized as safe and effective contrast agents for MRI. Because the efficacy of passively targeted iron particles remains variable, it was hypothesized that iron particles targeted to oxidation-specific epitopes might increase the utility of this platform.
  
  
  METHODS
  Lipid-coated ultra-small superparamagnetic iron particles (LUSPIOs) (<20 nm) and superparamagnetic iron particles (<40 nm) were conjugated with antibodies targeted to either malondialdehyde-lysine or oxidized phospholipid epitopes. All formulations were characterized, and their in vivo efficacy evaluated in apolipoprotein E deficient mice 24 h after bolus administration of a 3.9-mg Fe/kg dose with MRI. In vivo imaging data were correlated with the presence of oxidation-specific epitopes with immunohistochemistry.
  
  
  RESULTS
  MRI of atherosclerotic lesions, as manifested by signal loss, was observed after administration of targeted LUSPIOs. Immunohistochemistry confirmed the presence of malondialdehyde-epitopes and iron particles. Limited signal attenuation was observed for untargeted LUSPIOs. Additionally, no significant arterial wall uptake was observed for targeted or untargeted lipid-coated superparamagnetic iron oxide particles, due to their limited ability to penetrate the vessel wall.
  
  
  CONCLUSIONS
  This study demonstrates that LUSPIOs targeted to oxidation-specific epitopes image atherosclerotic lesions and suggests a clinically translatable platform for the detection of atherosclerotic plaque.
authors.affiliation: Translational and Molecular Imaging Institute, Department of Radiology, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Karen C
authors.initials: KC
authors.lastname: Briley-Saebo
authors.forename: Young Seok
authors.initials: YS
authors.lastname: Cho
authors.forename: Peter X
authors.initials: PX
authors.lastname: Shaw
authors.forename: Sung Kee
authors.initials: SK
authors.lastname: Ryu
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Mani
authors.forename: Stephen
authors.initials: S
authors.lastname: Dickson
authors.forename: Ehsan
authors.initials: E
authors.lastname: Izadmehr
authors.forename: Simone
authors.initials: S
authors.lastname: Green
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D050197:Atherosclerosis / Q000175:diagnosis* / Q000378:metabolism; D003287:Contrast Media / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods*; D000939:Epitopes / Q000008:administration & dosage / Q000276:immunology*; D005290:Ferric Compounds / Q000008:administration & dosage / Q000276:immunology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D010316:Particle Size
chemical_list: D000906:Antibodies; D003287:Contrast Media; D000939:Epitopes; D005290:Ferric Compounds; C000499:ferric oxide