title: Manganese G8 dendrimers targeted to oxidation-specific epitopes: in vivo MR imaging of atherosclerosis.
abstract: OBJECTIVE
  To determine if manganese (Mn) G8 dendrimers targeted to oxidation-specific epitopes (OSE) allow for in vivo detection of atherosclerotic lesions.
  
  
  METHODS
  OSE have been identified as key factors in atherosclerotic plaque progression and destabilization. Mn offers a potentially clinically translatable alternative to gadolinium-based agents when bioretention and potential toxicity of gadolinium is anticipated. However, to be effective, high payloads of Mn must accumulate intracellularly in macrophages. It was hypothesized that G8 dendrimers targeted to OSE may allow delivery of high Mn payloads, thereby enabling in vivo detection of macrophage-rich plaques. G8 dendrimers were modified to allow conjugation with MnDTPA (758 Mn ion) and the antibody MDA2 that is targeted to malondialdehyde (MDA)-lysine epitopes. Both the untargeted and targeted G8 dendrimers were characterized and their in vivo efficacy evaluated in apoE(-/-) mice over a 96-hour time period after bolus administration of a 0.05 mmol Mn/kg dose using a clinical MR system (3T).
  
  
  RESULTS
  Significant enhancement (normalized enhancement >60%, P = 0.0013) of atherosclerotic lesions was observed within a 72-hour time period following administration of the targeted dendrimers. The presence of Mn within atherosclerotic lesions was confirmed using spectroscopic methods (>8 μg Mn/g). Limited signal attenuation (<18%) and Mn deposition (<1 μg Mn/g) was observed in the arterial wall following injection of the untargeted material.
  
  
  CONCLUSIONS
  This study demonstrates that manganese-labeled dendrimers, allowing a high Mn payload, targeted to OSE may allow in vivo image of atherosclerotic lesions.
authors.affiliation: Translational and Molecular Imaging Institute and Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Tuyen H
authors.initials: TH
authors.lastname: Nguyen
authors.forename: Henry
authors.initials: H
authors.lastname: Bryant
authors.forename: Ari
authors.initials: A
authors.lastname: Shapsa
authors.forename: Hannah
authors.initials: H
authors.lastname: Street
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Mani
authors.forename: Zahi A
authors.initials: ZA
authors.lastname: Fayad
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Frank
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.forename: Karen C
authors.initials: KC
authors.lastname: Briley-Saebo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D050197:Atherosclerosis / Q000175:diagnosis*; D050091:Dendrimers; D004195:Disease Models, Animal; D000939:Epitopes; D009682:Magnetic Resonance Spectroscopy; D008345:Manganese; D051379:Mice; D008810:Mice, Inbred C57BL; D058226:Plaque, Atherosclerotic / Q000473:pathology
chemical_list: D050091:Dendrimers; D000939:Epitopes; D008345:Manganese
keywords: G8 dendrimers; manganese; oxidation-specific epitopes