Translational and Molecular Imaging Institute, Department of Radiology, Mount Sinai School of Medicine, New York, New York, USA.
J Am Coll Cardiol. 2011 Jan 18;57(3):337-47. doi: 10.1016/j.jacc.2010.09.023. Epub 2010 Nov 23.
OBJECTIVES: The aim of this study was to determine whether iron oxide particles targeted to oxidation-specific epitopes image atherosclerotic lesions. BACKGROUND: Oxidized low-density lipoprotein plays a major role in atherosclerotic plaque progression and destabilization. Prior studies indicate that gadolinium micelles labeled with oxidation-specific antibodies allow for in vivo detection of vulnerable plaques with magnetic resonance imaging (MRI). However, issues related to biotransformation/retention of gadolinium might limit clinical translation. Iron oxides are recognized as safe and effective contrast agents for MRI. Because the efficacy of passively targeted iron particles remains variable, it was hypothesized that iron particles targeted to oxidation-specific epitopes might increase the utility of this platform. METHODS: Lipid-coated ultra-small superparamagnetic iron particles (LUSPIOs) (<20 nm) and superparamagnetic iron particles (<40 nm) were conjugated with antibodies targeted to either malondialdehyde-lysine or oxidized phospholipid epitopes. All formulations were characterized, and their in vivo efficacy evaluated in apolipoprotein E deficient mice 24 h after bolus administration of a 3.9-mg Fe/kg dose with MRI. In vivo imaging data were correlated with the presence of oxidation-specific epitopes with immunohistochemistry. RESULTS: MRI of atherosclerotic lesions, as manifested by signal loss, was observed after administration of targeted LUSPIOs. Immunohistochemistry confirmed the presence of malondialdehyde-epitopes and iron particles. Limited signal attenuation was observed for untargeted LUSPIOs. Additionally, no significant arterial wall uptake was observed for targeted or untargeted lipid-coated superparamagnetic iron oxide particles, due to their limited ability to penetrate the vessel wall. CONCLUSIONS: This study demonstrates that LUSPIOs targeted to oxidation-specific epitopes image atherosclerotic lesions and suggests a clinically translatable platform for the detection of atherosclerotic plaque.
目的：本研究旨在确定针对氧化特异性表位的氧化铁颗粒是否能对动脉粥样硬化病变进行成像。
背景：氧化型低密度脂蛋白在动脉粥样硬化斑块的进展和不稳定中起着重要作用。先前的研究表明，用氧化特异性抗体标记的钆胶束允许用磁共振成像（MRI）对易损斑块进行体内检测。然而，与镧系元素的生物转化/保留相关的问题可能会限制临床转化。氧化铁被认为是磁共振成像的安全有效的对比剂。由于被动靶向铁颗粒的效果仍然存在差异，因此假设针对氧化特异性表位的铁颗粒可能会提高该平台的效用。
方法：脂质包被的超小超顺磁性氧化铁颗粒（LUSPIOs）（<20nm）和超顺磁性氧化铁颗粒（<40nm）与针对丙二醛-赖氨酸或氧化磷脂表位的抗体结合。所有制剂均进行了特征描述，并在载脂蛋白 E 缺陷小鼠中进行了体内研究，在给予 3.9mg Fe/kg 剂量的脂质包被的超小超顺磁性氧化铁颗粒后 24 小时，用 MRI 进行评估。体内成像数据与氧化特异性表位的免疫组化进行了相关性分析。
结果：给予靶向 LUSPIOs 后，动脉粥样硬化病变的 MRI 表现为信号丢失。免疫组化证实了丙二醛表位和铁颗粒的存在。未靶向 LUSPIOs 则观察到有限的信号衰减。此外，由于穿透血管壁的能力有限，靶向或未靶向的脂质包被超顺磁性氧化铁颗粒在动脉壁中均未观察到明显的摄取。
结论：本研究表明，针对氧化特异性表位的 LUSPIOs 可对动脉粥样硬化病变进行成像，并为检测动脉粥样硬化斑块提供了一种具有临床转化潜力的平台。
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