Immuno-PET of tissue factor in pancreatic cancer.
Immuno-PET of tissue factor in pancreatic cancer.
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DOI：
10.2967/jnumed.112.105460
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发表时间：
2012-11
期刊：
影响因子：
--
通讯作者：
Cai W
中科院分区：
文献类型：
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作者：
Hong H;Zhang Y;Nayak TR;Engle JW;Wong HC;Liu B;Barnhart TE;Cai W
在许多实体肿瘤类型中，组织因子(TF)表达上调导致患者发病率和死亡率增加。这项研究的目的是开发一种正电子发射断层扫描(PET)示踪剂，用于胰腺癌组织中TF表达的成像。将抗人转铁蛋白的嵌合单抗ALT-836与2-S-(4-异硫氰基苯甲基)-1，4，7-三氮杂环烷-1，4，7-三乙酸(p-SCN-Bn-NOTA)偶联，并用64Cu标记。为了比较ALT-836和NOTA-ALT-836与Tf结合的亲和力，用流式细胞术分析了三种不同Tf表达水平的胰腺癌细胞株(从低到高依次为：PANC-1、ASPC-1、BXPC-3)。在荷瘤小鼠上进行了PET成像、生物分布、阻断和组织学研究，以评价64Cu-NOTA-ALT-836体内靶向Tf的能力和特异性。ALT-836与NOTA-ALT-836的Tf结合亲和力无差异。实现了高产率和高比活性的64Cu标记。系列PET显像显示高表达Tf的BXPC-3肿瘤在注射后4、24和48h摄取~(64)Cu-NOTA-ALT-836分别为5.7±0.5、10.3±0.5和16.5±2.6%ID/g(n=4)，显著高于PANC-1和ASPC-1肿瘤。伽马计数测量的生物分布数据与PET结果一致。阻断实验和组织学进一步证实了64Cu-NOTA-ALT-836的转铁蛋白特异性。在此，我们报告了第一次成功的TF表达的PET成像。在胰腺癌模型中观察到了对64Cu-NOTA-ALT-836的持续摄取和Tf特异性摄取。
Upregulation of tissue factor (TF) expression leads to increased patient morbidity and mortality in many solid tumor types. The goal of this study was to develop a positron emission tomography (PET) tracer for imaging of TF expression in pancreatic cancer. ALT-836, a chimeric anti-human TF monoclonal antibody, was conjugated to 2-S-(4-isothiocyanatobenzyl)-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (p-SCN-Bn-NOTA) and labeled with 64Cu. To compare the TF binding affinity of ALT-836 and NOTA-ALT-836, flow cytometry analysis was performed in three pancreatic cancer cell lines with different expression level of TF (from low to high: PANC-1, ASPC-1, and BXPC-3). PET imaging, biodistribution, blocking, and histology studies were performed on pancreatic tumor-bearing mice to evaluate the ability and specificity of 64Cu-NOTA-ALT-836 to target TF in vivo. There was no difference in TF binding affinity between ALT-836 and NOTA-ALT-836. 64Cu-labeling was achieved with high yield and specific activity. Serial PET imaging revealed that the uptake of 64Cu-NOTA-ALT-836 in BXPC-3 tumors (high TF expression) was 5.7 ± 0.5, 10.3 ± 0.5, and 16.5 ± 2.6 %ID/g at 4, 24, and 48 h post-injection respectively (n = 4), significantly higher than that in the PANC-1 and ASPC-1 tumors. Biodistribution data as measured by gamma counting were consistent with the PET findings. Blocking experiments and histology further confirmed the TF specificity of 64Cu-NOTA-ALT-836. Herein we report the first successful PET imaging of TF expression. Persistent and TF-specific uptake of 64Cu-NOTA-ALT-836 was observed in pancreatic cancer models.