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.
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 (99m)Tc-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 (99m)Tc after derivatization with 6-hydrazinonicotinic acid to yield (99m)Tc-LOX-1-mAb and (99m)Tc-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 (99m)Tc-LOX-1-mAb accumulation was 2.0-fold higher than the level of (99m)Tc-IgG2a accumulation in WHHLMI rabbit aortas, and the level of (99m)Tc-LOX-1-mAb accumulation in WHHLMI rabbit aortas was 10.0-fold higher than the level of (99m)Tc-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 (99m)Tc-IgG2a accumulation was independent of the histologic grade of the lesions; however, regional (99m)Tc-LOX-1-mAb accumulation was significantly correlated with LOX-1 expression density and the vulnerability index. The highest level of (99m)Tc-LOX-1-mAb accumulation, expressed as {radioactivity in region of interest (Bq/mm(2))/[injected radioactivity (Bq)/animal body weight (g)]} x 10(2), 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).


CONCLUSIONS
The level of (99m)Tc-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 (99m)Tc-LOX-1-mAb may be a useful means for predicting atheroma at high risk for rupture.
Ishino
Seigo
S
Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Mukai
Takahiro
T
Kuge
Yuji
Y
Kume
Noriaki
N
Ogawa
Mikako
M
Takai
Nozomi
N
Kamihashi
Junko
J
Shiomi
Masashi
M
Minami
Manabu
M
Kita
Toru
T
Saji
Hideo
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000175:diagnosis* / Q000000981:diagnostic imaging*; D003952:Diagnostic Imaging / Q000379:methods; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000494:pharmacology; D006949:Hyperlipidemias / Q000175:diagnosis / Q000473:pathology; D007074:Immunoglobulin G / Q000737:chemistry; D008297:Male; D011817:Rabbits; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000494:pharmacology; D051127:Scavenger Receptors, Class E / Q000737:chemistry* / Q000378:metabolism; D013667:Technetium / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D019275:Radiopharmaceuticals; D051127:Scavenger Receptors, Class E; D019788:Fluorodeoxyglucose F18; D013667:Technetium