ENT-Department, Section of Experimental Oncology Und Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-Professorship, Universitätsklinikum Erlangen, Erlangen, Germany.
Institute of Radiology, Universitätsklinikum Erlangen, Erlangen, Germany.
Int J Nanomedicine. 2024 Feb 20;19:1645-1666. doi: 10.2147/IJN.S430693. eCollection 2024.
In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI).
The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPION and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPION was evaluated in rats.
Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPION and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPION administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg.
Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPION particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.
本研究通过对兔动脉粥样硬化模型进行详细特征描述，评估超顺磁性氧化铁纳米颗粒（SPION）增强磁共振成像（MRI）评估斑块易损性的最佳时间框架。
采用血管造影术监测球囊扩张和高胆固醇饮食诱导的动脉粥样硬化进展，并用免疫组织化学和组织学方法对形成的斑块进行特征描述。进行形态计量学分析以评估斑块大小和易损性特征。通过组织学和 MRI 研究评估 SPION（新型葡聚糖包裹的 SPION 和 ferumoxytol）在动脉粥样硬化斑块中的积累情况，并与斑块年龄和易损性相关联。评估 SPION 在大鼠中的毒性。
检测到斑块年龄与内膜厚度和总巨噬细胞负荷呈弱正相关，最小纤维帽厚度与斑块年龄和平均巨噬细胞负荷呈强负相关。MRI 检测到 SPION 在动脉粥样硬化斑块中的积累，随后通过普鲁士蓝染色的组织学标本得到证实。在动脉粥样硬化斑块中检测到普鲁士蓝信号与斑块年龄和巨噬细胞负荷之间存在正相关。在心脏和肾脏的组织学切片中几乎观察不到铁，而在脾脏和肝脏中则观察到 SPION 和 ferumoxytol 的强烈染色。与 ferumoxytol 相比，SPION 在兔中的给药具有良好的耐受性，不会引起过敏反应。在大鼠模型中，最大耐受剂量高于 100mg Fe/kg。
具有易损特征的较陈旧的兔动脉粥样硬化斑块是研究 MRI 用氧化铁基对比剂的有用工具。基于实验数据，SPION 颗粒构成了一种有前途的候选物，可进一步临床转化为一种安全的制剂，可重复给药，而不会带来其他类型的磁性对比剂相关的风险。
