Receptor-binding, biodistribution, and metabolism studies of 64Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors
Receptor-binding, biodistribution, and metabolism studies of 64Cu-DOTA-cetuximab, a PET-imaging agent for epidermal growth-factor receptor-positive tumors
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DOI：
10.1089/cbr.2007.0444
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发表时间：
2008-04-01
影响因子：
3.4
通讯作者：
Anderson, Carolyn J.
中科院分区：
文献类型：
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作者：
Li, Wen Ping;Meyer, Laura A.;Anderson, Carolyn J.
表皮生长因子受体（EGFR）及其配体在肿瘤发生的病理生理过程中起着重要作用。EGFR的过表达在多种实体人类癌症的肿瘤进展中起重要作用。因此，EGFR代表了用于癌症的新型诊断和治疗剂的设计的有吸引力的靶标。西妥昔单抗（C225，爱必妥（（R）是第一个针对EGFR配体结合位点的单克隆抗体，由食品和药物管理局批准用于治疗EGFR表达的转移性结直肠癌患者，尽管临床试验显示对这种治疗的反应存在差异。本研究的目的涉及使用西妥昔单抗设计一种正电子发射断层扫描（PET）剂，以成像肿瘤中EGFR的过度表达。将西妥昔单抗与螯合剂DOTA偶联，用于用正电子发射体（CU）-C-64进行放射性标记（T-1/2 = 12.7小时）。Cu-64-DOTA-西妥昔单抗显示出与EGFR阳性A431细胞的高结合亲和力（K-D为0.28 nM）。Cu-64-DOTA-西妥昔单抗的生物分布和microPET成像研究均显示，与EGFR阴性MDA-MB-435肿瘤（2.60%+/- 0.35% ID/g）相比，EGFR阳性A431肿瘤（18.49%+/- 6.50%注射剂量/克[ID/g]）在注射后24小时的摄取更高。A431肿瘤在24小时的摄取被未标记的西妥昔单抗阻断（10.69%+/-2.72%ID/g），表明肿瘤摄取是受体介导的。体内代谢实验表明，64 Cu-DOTA-西妥昔单抗在荷瘤小鼠血液中相对稳定，但在肝脏和肿瘤中有显著代谢。Cu-64-DOTA-西妥昔单抗是一种用于人类EGFR阳性肿瘤成像的潜在药物。
The epidermal growth-factor receptor (EGFR) and its ligands have been recognized as critical factors in the pathophysiology of tumorigenesis. Overexpression of the EGFR plays a significant role in the tumor progression of a wide variety of solid human cancers. Therefore, the EGFR represents an attractive target for the design of novel diagnostic and therapeutic agents for cancer. Cetuximab (C225, Erbitux((R))) was the first monoclonal antibody targeted against the ligand-binding site of EGFR approved by the Food and Drug Administration for the treatment of patients with EGFR-expressing, metastatic colorectal carcinoma, although clinical trials showed variability in the response to this treatment. The aim of this study involved using cetuximab to design a positron emission tomography (PET) agent to image the overexpression of EGFR in tumors. Cetuximab was conjugated with the chelator, DOTA, for radiolabeling with the positron-emitter, (CU)-C-64 (T-1/2 = 12.7 hours). Cu-64-DOTA-cetuximab showed high binding affinity to EGFR-positive A431 cells (K-D of 0.28 nM). Both biodistribution and microPET imaging studies with Cu-64-DOTA-cetuximab demonstrated greater uptake at 24 hours postinjection in EGFR-positive A431 tumors (18.49%+/- 6.50% injected dose per gram [ID/g]), compared to EGFR-negative MDA-MB-435 tumors (2.60%+/- 0.35% ID/g). A431 tumor uptake at 24 hours was blocked with unlabeled cetuximab (10.69%+/- 2.72% ID/g), suggesting that the tumor uptake was receptor mediated. Metabolism experiments in vivo showed that 64Cu-DOTA-cetuximab was relatively stable in the blood of tumor-bearing mice; however, there was significant metabolism in the liver and tumors. Cu-64-DOTA-cetuximab is a potential agent for imaging EGFR-positive tumors in humans.