Synthesis of acid-stabilized iron oxide nanoparticles and comparison for targeting atherosclerotic plaques: evaluation by MRI, quantitative MPS, and TEM alternative to ambiguous Prussian blue iron staining

Nanomedicine. 2015 Jul;11(5):1085-95. doi: 10.1016/j.nano.2015.01.002. Epub 2015 Feb 4.


To further optimize citrate-stabilized VSOPs (very small iron oxide particles, developed for MR angiography) for identification of atherosclerotic plaques, we modified their surface during synthesis using eight other acids for electrostatic stabilization. This approach preserves effective production for clinical application. Five particles were suitable to be investigated in targeting plaques of apoE(-/-) mice. Accumulation was evaluated by ex vivo MRI, TEM, and quantitatively by magnetic particle spectroscopy (MPS). Citric- (VSOP), etidronic-, tartaric-, and malic-acid-coated particles accumulated in atherosclerotic plaques with highest accumulation for VSOP (0.2‰ of injected dose). Targets were phagolysosomes of macrophages and of altered endothelial cells. In vivo MRI with VSOP allowed for definite plaque identification. Prussian blue staining revealed abundant endogenous iron in plaques, indistinguishable from particle iron. In apoE(-/-) mice, VSOPs are still the best anionic iron oxide particles for imaging atherosclerotic plaques. MPS allows for quantification of superparamagnetic nanoparticles in such small specimens.

From the clinical editor: The presence of vulnerable plaques in arteries is important for the prediction of acute coronary events. VSOP (very small iron oxide particles, developed for MR angiography) have been shown to be very sensitive in identifying atherosclerotic plaques. The authors studied here further modification to the surface of VSOP during synthesis and compared their efficacy.

Keywords: Atherosclerotic plaques; Ferumoxytol; Iron oxide particles; Magnetic particle spectroscopy; Magnetic resonance imaging.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / pathology*
  • Apolipoproteins E / genetics
  • Carotid Arteries / pathology
  • Citric Acid / chemistry
  • Etidronic Acid / chemistry
  • Ferric Compounds / chemistry*
  • Ferric Compounds / pharmacokinetics
  • Ferrocyanides / analysis
  • Magnetic Resonance Imaging
  • Magnetite Nanoparticles / analysis
  • Magnetite Nanoparticles / chemistry*
  • Malates / chemistry
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Plaque, Atherosclerotic / diagnosis
  • Plaque, Atherosclerotic / genetics
  • Plaque, Atherosclerotic / pathology*
  • Spectrum Analysis
  • Staining and Labeling
  • Tartrates / chemistry


  • Apolipoproteins E
  • Ferric Compounds
  • Ferrocyanides
  • Magnetite Nanoparticles
  • Malates
  • Tartrates
  • ferric oxide
  • Citric Acid
  • malic acid
  • Etidronic Acid
  • ferric ferrocyanide
  • tartaric acid