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

我们已经证明，超顺磁性非常小的氧化铁颗粒（VSOP）不仅非常适合于磁共振血管造影（MRA），而且可以非常灵敏地检测动脉粥样硬化斑块，与其他几种阴离子纳米颗粒相比，它们被发现是最合适的。与空间稳定的氧化铁纳米颗粒（例如，阿魏木糖醇，已被批准用于铁替代治疗）不同，VSOP由于其快速动力学，具有在单次MR成像过程中在不到3小时内进行MRA和斑块联合成像的潜力。最近，我们已经证明，与现有的方法（例如普鲁士蓝铁染色，内源性组织铁不特异性）相比，铕点VSOP （Eu-VSOP）与激光烧蚀电感耦合等离子体质谱（LA-ICP-MS）的结合首次允许对组织切片中的氧化铁纳米颗粒进行选择性、敏感性和定量鉴定。在拟议的项目中，我们打算使用这种组合来研究炎症和易损的典型标记与动脉粥样硬化斑块中VSOP积累相关，以及内源性或颗粒铁区域是否含有活性氧（ROS）。当抗体用不同的类镧标记时，该技术允许在同一组织切片中同时将多个标记物与Eu-VSOP相关联（多路复用）。为了进行比较，计划进行常规免疫组织学染色，然后（在去除盖片后）用LA-ICP-MS进一步研究这些制剂。最后，Eu-VSOP将通过在铕通道中应用ICP-MS用于器官分布的非放射性测定。这些研究对于了解VSOP在斑块中的积累和VSOP的临床翻译具有重要意义。

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.