Positron Emission Tomography Imaging of Vascular Endothelial Growth Factor Receptor Expression with 61Cu-Labeled Lysine-Tagged VEGF121
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- 作者：Yin Zhang ; Hao Hong ; Gang Niu ; Hector F. Valdovinos ; Hakan Orbay ; Tapas R. Nayak ; Xiaoyuan Chen ; Todd E. Barnhart ; Weibo Cai
- 刊名：Molecular Pharmaceutics
- 出版年：2012
- 出版时间：December 3, 2012
- 年：2012
- 卷：9
- 期：12
- 页码：3586-3594
- 全文大小：383K
- 年卷期：v.9,no.12(December 3, 2012)
- ISSN：1543-8392
文摘
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 61Cu (t1/2: 3.3 h; 62% 尾+). The IC50 value of NOTA鈥揔3-VEGF121 for VEGFR-2 was comparable to that of K3-VEGF121 (1.50 and 0.65 nM, respectively) based on a cell binding assay. 61Cu labeling was achieved with good yield (55 卤 10%) and specific activity (4.2 GBq/mg). Serial PET imaging showed that the 4T1 tumor uptake of 61Cu鈥揘OTA鈥揔3-VEGF121 was 3.4 卤 0.5, 4.9 卤 1.0, 5.2 卤 1.0, and 4.8 卤 0.8%ID/g (n = 4) at 0.5, 2, 4, and 8 h postinjection, respectively, which was consistent with biodistribution data measured by 纬 counting. Blocking experiments and ex vivo histology confirmed the VEGFR specificity of 61Cu鈥揘OTA鈥揔3-VEGF121. Extrapolated human dosimetry calculation showed that liver was the organ with the highest radiation dose. The use of 61Cu as the radiolabel is desirable for small proteins such as K3-VEGF121, which has a much higher 尾+ branching ratio than the commonly used 64Cu (62% vs 17%), thereby offering stronger signal intensity and lower tracer dose for PET imaging.