PET of vascular endothelial growth factor receptor expression.
For solid tumors and metastatic lesions, tumor vascularity is a critical factor in assessing response to therapy. Here we report the first example, to our knowledge, of (64)Cu-labeled vascular endothelial growth factor 121 (VEGF(121)) for PET of VEGF receptor (VEGFR) expression in vivo.


METHODS
VEGF(121) was conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and then labeled with (64)Cu for small-animal PET of mice bearing different sized U87MG human glioblastoma xenografts. Blocking experiments and ex vivo histopathology were performed to confirm the in vivo results.


RESULTS
There were 4.3 +/- 0.2 DOTA molecules per VEGF(121), and the VEGFR2 binding affinity of DOTA-VEGF(121) was comparable to VEGF(121). (64)Cu labeling of DOTA-VEGF(121) was achieved in 90 +/- 10 min and the radiolabeling yield was 87.4% +/- 3.2%. The specific activity of (64)Cu-DOTA-VEGF(121) was 3.2 +/- 0.1 GBq/mg with a radiochemical purity of >98%. Small-animal PET revealed rapid, specific, and prominent uptake of (64)Cu-DOTA-VEGF(121) in small U87MG tumors (high VEGFR2 expression) but significantly lower and sporadic uptake in large U87MG tumors (low VEGFR2 expression). No appreciable renal clearance of (64)Cu-DOTA-VEGF(121) was observed, although the kidney uptake was relatively high likely due to VEGFR1 expression. Blocking experiments, immunofluorescence staining, and western blot confirmed the VEGFR specificity of (64)Cu-DOTA-VEGF(121).


CONCLUSIONS
Successful demonstration of the ability of (64)Cu-DOTA-VEGF(121) to visualize VEGFR expression in vivo may allow for clinical translation of this radiopharmaceutical for imaging tumor angiogenesis and guiding antiangiogenic treatment, especially patient selection and treatment monitoring of VEGFR-targeted cancer therapy.
Cai
Weibo
W
Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA 94305-5484, USA.
Chen
Kai
K
Mohamedali
Khalid A
KA
Cao
Qizhen
Q
Gambhir
Sanjiv S
SS
Rosenblum
Michael G
MG
Chen
Xiaoyuan
X
D000818:Animals; D045744:Cell Line, Tumor; D003301:Copper Radioisotopes / Q000493:pharmacokinetics; D015870:Gene Expression; D005909:Glioblastoma / Q000098:blood supply / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D008657:Metabolic Clearance Rate; D051379:Mice; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000378:metabolism; D009928:Organ Specificity; D049268:Positron-Emission Tomography / Q000379:methods*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D014018:Tissue Distribution; D042461:Vascular Endothelial Growth Factor A / Q000493:pharmacokinetics*
D003301:Copper Radioisotopes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor