Quantitative Correlation of the MR-Angiography and Atherosclerosis Probe VSOP in Atherosclerotic Plaques with Markers for PlaqueInstability by Element Microscopy (LA-ICP-MS)

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We have shown that superparamagnetic very small iron oxide particles (VSOP) are not only well suited for magnetic resonance angiography (MRA) but also allow very sensitive detection of atherosclerotic plaques, for which they have been found to be most suitable compared with several other anionic nanoparticles. Unlike sterically stabilized iron oxide nanoparticles (e.g., ferumoxytol, approved for iron replacement therapy) VSOP have due to their fast kinetics the potential for performing combined MRA and plaque imaging in less than 3 hours in a single MR imaging session.Recently, we have shown that, in contrast to established methods, (e.g., Prussian blue iron staining, unspecific with endogenous tissue iron) the combination of Europium-doted VSOP (Eu-VSOP) with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) for the first time allows selective, sensitive, and quantitative identification of iron oxide nanoparticles in tissue sections. In the proposed project, we intend to use this combination to investigate which typical markers of inflammation and vulnerability correlate with VSOP accumulation in atherosclerotic plaques and whether areas with endogenous or particle iron contain reactive oxygen species (ROS). When antibodies are labeled with different lanthanoids, this technique allows simultaneous correlation of several markers with Eu-VSOP in the same tissue section (multiplexing). For comparison, it is planned to perform conventional immunohistological staining and to then (after removal of the cover slips) additionally investigate these preparations with LA-ICP-MS. Finally, the Eu-VSOP will be used for nonradioactive determination of organ distribution by applying ICP-MS in the Europium channel. These investigations are highly relevant for understanding VSOP accumulation in plaques and for clinical translation of VSOP.