Targeting of Lectinlike Oxidized Low-Density Lipoprotein Receptor 1 (LOX-1) with 99mTc-Labeled Anti–LOX-1 Antibody: Potential Agent for Imaging of Vulnerable Plaque
Seigo Ishino 1,
Takahiro Mukai 2,
Yuji Kuge 1,
Noriaki Kume 3,
Mikako Ogawa 4,
Nozomi Takai 1,
Junko Kamihashi 1,
Masashi Shiomi 5,
Manabu Minami 3,
Toru Kita 3,
and
Hideo Saji 1*
1 Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
2 Department of Biomolecular Recognition Chemistry, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
3 Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
4 Laboratory of Genome Bio-Photonics Photon Medical Research Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
5 Institute for Experimental Animals, Kobe University School of Medicine, Kobe, Japan
* To whom correspondence should be addressed. E-mail: hsaji{at}pharm.kyoto-u.ac.jp.
 |
Abstract |
|---|
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 99mTc-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 99mTc after derivatization with 6-hydrazinonicotinic acid to yield 99mTc-LOX-1-mAb and 99mTc-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 99mTc-LOX-1-mAb accumulation was 2.0-fold higher than the level of 99mTc-IgG2a accumulation in WHHLMI rabbit aortas, and the level of 99mTc-LOX-1-mAb accumulation in WHHLMI rabbit aortas was 10.0-fold higher than the level of 99mTc-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 99mTc-IgG2a accumulation was independent of the histologic grade of the lesions; however, regional 99mTc-LOX-1-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/mm2)/[injected radioactivity (Bq)/animal body weight (g)]} x 102, was found in atheromatous lesions (3.8 ± 1.1 [mean ± SD]), 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 99mTc-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 99mTc-LOX-1-mAb may be a useful means for predicting atheroma at high risk for rupture.
Key Words:
plaque, receptor, antibody, imaging, atherosclerosis
