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PET of Vascular Endothelial Growth Factor Receptor Expression

¹ Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California; ² Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas; and ³ Department of Bioengineering, Stanford University, Stanford, California

Correspondence: For correspondence or reprints contact: Xiaoyuan Chen, PhD, Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, 1201 Welch Rd., P095, Stanford, CA 94305-5484. E-mail: shawchen{at}stanford.edu

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 ⁶⁴Cu-labeled vascular endothelial growth factor 121 (VEGF₁₂₁) for PET of VEGF receptor (VEGFR) expression in vivo. Methods: VEGF₁₂₁ was conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) and then labeled with ⁶⁴Cu 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 VEGF₁₂₁, and the VEGFR2 binding affinity of DOTA-VEGF₁₂₁ was comparable to VEGF₁₂₁. ⁶⁴Cu labeling of DOTA-VEGF₁₂₁ was achieved in 90 ± 10 min and the radiolabeling yield was 87.4% ± 3.2%. The specific activity of ⁶⁴Cu-DOTA-VEGF₁₂₁ was 3.2 ± 0.1 GBq/mg with a radiochemical purity of >98%. Small-animal PET revealed rapid, specific, and prominent uptake of ⁶⁴Cu-DOTA-VEGF₁₂₁ 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 ⁶⁴Cu-DOTA-VEGF₁₂₁ 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 ⁶⁴Cu-DOTA-VEGF₁₂₁. Conclusion: Successful demonstration of the ability of ⁶⁴Cu-DOTA-VEGF₁₂₁ 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.

Key Words: vascular endothelial growth factor • Flk-1/KDR (vascular endothelial growth factor receptor 2) • PET • tumor vasculature • ⁶⁴Cu

^* Contributed equally to this work.

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