Positron emission tomography imaging and biodistribution of vascular endothelial growth factor with 64Cu-labeled bevacizumab in colorectal cancer xenografts.
Vascular endothelial growth factor (VEGF) is considered to be a major angiogenic factor responsible for the development of tumor vasculature. The aim of this study was to image VEGF expression with (64)Cu-labeled anti-VEGF antibody (bevacizumab) non-invasively, and to see whether or not the expression was correlated with tumor accumulation in colorectal cancer xenografts. Bevacizumab was conjugated with the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) and radiolabeled with (64)Cu. In vivo biodistribution studies and positron emission tomography (PET) imaging were performed on mice bearing human colorectal cancer (HT29) xenografts after injection of (64)Cu-DOTA-bevacizumab, which showed clear accumulation of (64)Cu-DOTA-bevacizumab in the tumor (22.7 ± 1.0 %ID/g, 24 ± 0.2 %ID/g, 19.0 ± 2.5 %ID/g at 24, 48 and 72 h, respectively). Tumor accumulation of (64)Cu-DOTA-bevacizumab was significantly correlated with VEGF expression as measured by western blot (ρ = 0.81, P = 0.004). Vascular endothelial growth factor blocking with unlabeled bevacizumab significantly reduced tumor accumulation of (64) Cu-DOTA- bevacizumab (9.7 ± 1.2 %ID/g, P < 0.001) at 48 h. Interestingly, the blood concentration of VEGF in the mice treated with excess fold of bevacizumab was significantly higher than those without at 48 h (25.5 ± 4.6 %ID/g vs 6.5 ± 2.1 %ID/g, P = 0.0016). Liver uptake decreased from 24 h (17.2 ± 1.7 %ID/g) to 48 h (13.0 ± 4.2 %ID/g) and 72 h (10.6 ± 1.5 %ID/g) due to hepatic clearance of the tracer. The present study successfully showed (64) Cu-DOTA-bevacizumab as a potential PET tracer for non-invasive imaging of VEGF expression in colorectal cancer xenografts.
Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Gunma, Japan. paudyal@med.gunma-u.ac.jp
Bishnuhari
B
Paudyal
Pramila
P
Paudyal
Noboru
N
Oriuchi
Hirofumi
H
Hanaoka
Hideyuki
H
Tominaga
Keigo
K
Endo
D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D015153:Blotting, Western; D003301:Copper Radioisotopes; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D007553:Isotope Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D014018:Tissue Distribution; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis* / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003301:Copper Radioisotopes; D019275:Radiopharmaceuticals; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab