title: Positron emission tomography imaging of vascular endothelial growth factor receptor expression with (61)Cu-labeled lysine-tagged VEGF121.
abstract: Overexpression of vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) indicates poor prognosis for cancer patients in a variety of clinical studies. Our goal is to develop a tracer for positron emission tomography (PET) imaging of VEGFR expression using recombinant human VEGF121 with three lysine residues fused to the N-terminus (denoted as K3-VEGF121), which can facilitate radiolabeling without affecting its VEGFR binding affinity. K3-VEGF121 was conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) and labeled with (61)Cu (t1/2: 3.3 h; 62% β(+)). The IC50 value of NOTA-K3-VEGF121 for VEGFR-2 was comparable to that of K3-VEGF121 (1.50 and 0.65 nM, respectively) based on a cell binding assay. (61)Cu labeling was achieved with good yield (55 ± 10%) and specific activity (4.2 GBq/mg). Serial PET imaging showed that the 4T1 tumor uptake of (61)Cu-NOTA-K3-VEGF121 was 3.4 ± 0.5, 4.9 ± 1.0, 5.2 ± 1.0, and 4.8 ± 0.8%ID/g (n = 4) at 0.5, 2, 4, and 8 h postinjection, respectively, which was consistent with biodistribution data measured by γ counting. Blocking experiments and ex vivo histology confirmed the VEGFR specificity of (61)Cu-NOTA-K3-VEGF121. Extrapolated human dosimetry calculation showed that liver was the organ with the highest radiation dose. The use of (61)Cu as the radiolabel is desirable for small proteins such as K3-VEGF121, which has a much higher β(+) branching ratio than the commonly used (64)Cu (62% vs 17%), thereby offering stronger signal intensity and lower tracer dose for PET imaging.
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison , Wisconsin, United States.
authors.forename: Yin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Hao
authors.initials: H
authors.lastname: Hong
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Hector F
authors.initials: HF
authors.lastname: Valdovinos
authors.forename: Hakan
authors.initials: H
authors.lastname: Orbay
authors.forename: Tapas R
authors.initials: TR
authors.lastname: Nayak
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.forename: Weibo
authors.initials: W
authors.lastname: Cai
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D003301:Copper Radioisotopes; D005260:Female; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D057054:Molecular Imaging / Q000379:methods*; D009389:Neovascularization, Pathologic / Q000175:diagnosis; D049268:Positron-Emission Tomography / Q000379:methods*; D011874:Radiometry; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003301:Copper Radioisotopes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor; D008239:Lysine