Targeting of Lectinlike Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) with 99mTCLabeled Anti-LOX-1 Antibody: Potential Agent for Imaging of Vulnerable Plaque
Targeting of Lectinlike Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) with 99mTCLabeled Anti-LOX-1 Antibody: Potential Agent for Imaging of Vulnerable Plaque
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DOI：
10.2967/jnumed.107.049536
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发表时间：
2008-10-01
影响因子：
9.3
通讯作者：
Saji, Hideo
中科院分区：
文献类型：
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作者：
Ishino, Seigo;Mukai, Takahiro;Saji, Hideo
凝集素样氧化低密度脂蛋白（LDL）受体1（LOX-1），氧化低密度脂蛋白的细胞表面受体，已被牵连在血管细胞功能障碍相关的斑块不稳定性，这可能是动脉粥样硬化成像示踪剂的潜在目标。在这项研究中，我们设计并制备了Tc-99 m标记的抗LOX-1单克隆IgG，并研究其作为动脉粥样硬化显像剂的有用性。研究方法：抗LOX-1单克隆IgG和对照小鼠IgG 2a经6-肼基烟酸衍生后用Tc-99 m标记，分别得到Tc-99 m-LOX-1-mAb和Tc-99 m-IgG 2a。心肌梗死倾向的渡边遗传性高血压（WHHLMI）兔（动脉粥样硬化模型）和对照兔静脉注射这些探针，并在体内平面成像进行。在注射后24小时，取出睾丸，并测量放射性。放射自显影和组织学研究进行了连续的主动脉切片。结果如下：在WHHLMI兔胸腺中，Tc-99 m-LOX-1-mAb的蓄积水平是Tc-99 m-IgG 2a蓄积水平的2.0倍，而在WHHLMI兔胸腺中，Tc-99 m-LOX-1-mAb的蓄积水平是对照兔胸腺中Tc-99 m-LOX-1-mAb蓄积水平的10.0倍。在体内成像清楚地显示了WHHLMI兔的动脉粥样硬化斑块。放射自显影和组织学研究表明，局部Tc-99 m-IgG 2a蓄积与病变的组织学分级无关;然而，局部Tc-99 m-LOX 1-mAb蓄积与LOX-1表达密度和易损性指数显著相关。99 mTc-LOX-1-mAb蓄积的最高水平，表示为{感兴趣区域的放射性（Bq/mm（2））/[注射放射性（Bq）/动物体重（g）]} × 102，在动脉粥样硬化病变中发现（3.8 +/- 1.1 [平均值+/- SID]），其次为纤维动脉粥样硬化病变，降序排列（2.0 +/- 1.0）、富含胶原病变（1.6 +/- 0.8）和新生内膜病变（1.4（+/-）0.7）。结论：IV级动脉粥样硬化中Tc-99 m-LOX-1-mAb的蓄积水平高于新生内膜病变或其他更稳定的病变。用Tc-99 m-LOX-1-mAb进行LOX-1表达的核成像可能是预测动脉粥样硬化破裂高危的有用手段。
Lectinlike oxidized low-density lipoprotein (LDL) receptor 1 (LOX-1), a cell surface receptor for oxidized LDL, has been implicated in vascular cell dysfunction related to plaque instability, which could be a potential target for an atherosclerosis imaging tracer. In this study, we designed and prepared Tc-99m-labeled anti-LOX-1 monoclonal IgG and investigated its usefulness as an atherosclerosis imaging agent. Methods: Anti-LOX-1 monoclonal IgG and control mouse IgG2a were labeled with Tc-99m after derivatization with 6-hydrazinonicotinic acid to yield Tc-99m-LOX-1-mAb and Tc-99m-IgG2a, respectively. Myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits (atherosclerosis model) and control rabbits were injected intravenously with these probes, and in vivo planar imaging was performed. At 24 h after the injection, the aortas were removed, and radioactivity was measured. Autoradiography and histologic studies were performed with serial aortic sections. Results: The level of Tc-99m-LOX-1-mAb accumulation was 2.0-fold higher than the level of Tc-99m-IgG2a accumulation in WHHLMI rabbit aortas, and the level of Tc-99m-LOX-1-mAb accumulation in WHHLMI rabbit aortas was 10.0-fold higher than the level of Tc-99m-LOX-1-mAb accumulation in control rabbit aortas. In vivo imaging clearly visualized the atherosclerotic aortas of WHHLMI rabbits. Autoradiography and histologic studies revealed that regional Tc-99m-IgG2a accumulation was independent of the histologic grade of the lesions; however, regional Tc-99m-LOX1-mAb accumulation was significantly correlated with LOX-1 expression density and the vulnerability index. The highest level of 99mTc-LOX-1-mAb accumulation, expressed as {radioactivity in region of interest (Bq/mm(2))/[injected radioactivity (Bq)/animal body weight (g)]} x 102, was found in atheromatous lesions (3.8 +/- 1.1 [mean +/- SID]), followed in decreasing order by fibroatheromatous lesions (2.0 +/- 1.0), collagen-rich lesions (1.6 +/- 0.8), and neointimal lesions (1.4 (+/-) 0.7). Conclusion: The level of Tc-99m-LOX-1-mAb accumulation in grade IV atheroma was higher than that in neointimal lesions or other, more stable lesions. Nuclear imaging of LOX-1 expression with Tc-99m-LOX-1-mAb may be a useful means for predicting atheroma at high risk for rupture.