Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 9 Memorial Drive, 9/1 W111, Bethesda, MD 20892, USA.
Eur J Nucl Med Mol Imaging. 2011 Oct;38(10):1806-15. doi: 10.1007/s00259-011-1871-4. Epub 2011 Aug 4.
Tumor endothelial marker 8 (TEM8) has been reported to be upregulated in both tumor cells and tumor-associated endothelial cells in several cancer types. TEM8 antagonists and TEM8-targeted delivery of toxins have been developed as effective cancer therapeutics. The ability to image TEM8 expression would be of use in evaluating TEM8-targeted cancer therapy.
A 13-meric peptide, KYNDRLPLYISNP (QQM), identified from the small loop in domain IV of protective antigen of anthrax toxin was evaluated for TEM8 binding and labeled with 18F for small-animal PET imaging in both UM-SCC1 head-and-neck cancer and MDA-MB-435 melanoma models.
A modified ELISA showed that QQM peptide bound specifically to the extracellular vWA domain of TEM8 with an IC50 value of 304 nM. Coupling 4-nitrophenyl 2-(18)F-fluoropropionate with QQM gave almost quantitative yield and a high specific activity (79.2±7.4 TBq/mmol, n=5) of 18F-FP-QQM at the end of synthesis. 18F-FP-QQM showed predominantly renal clearance and had significantly higher accumulation in TEM8 high-expressing UM-SCC1 tumors (2.96±0.84 %ID/g at 1 h after injection) than TEM8 low-expressing MDA-MB-435 tumors (1.38±0.56 %ID/g at 1 h after injection).
QQM peptide bound specifically to the extracellular domain of TEM8. 18F-FP-QQM peptide tracer would be a promising lead compound for measuring TEM8 expression. Further efforts to improve the affinity and specificity of the tracer and to increase its metabolic stability are warranted.
肿瘤内皮标志物 8（TEM8）已在多种癌症类型的肿瘤细胞和肿瘤相关内皮细胞中被报道上调。已经开发出 TEM8 拮抗剂和 TEM8 靶向毒素递送来作为有效的癌症治疗方法。能够对 TEM8 表达进行成像将有助于评估 TEM8 靶向癌症治疗。
从小肠结肠炎耶尔森氏菌毒素保护性抗原的 IV 结构域的小环中鉴定出 13 肽 KYNDRLPLYISNP（QQM），用于评估 TEM8 结合，并与 18F 标记用于 UM-SCC1 头颈部癌症和 MDA-MB-435 黑色素瘤模型中的小动物 PET 成像。
改良的 ELISA 显示 QQM 肽特异性结合 TEM8 的细胞外 vWA 结构域，IC50 值为 304 nM。将 4-硝基苯基 2-（18）F-氟丙酸盐与 QQM 偶联得到几乎定量的产率和高比活度（79.2±7.4 TBq/mmol，n=5）的 18F-FP-QQM，在合成结束时。18F-FP-QQM 主要通过肾脏清除，在 TEM8 高表达的 UM-SCC1 肿瘤（注射后 1 小时 2.96±0.84 %ID/g）中的积累明显高于 TEM8 低表达的 MDA-MB-435 肿瘤（注射后 1 小时 1.38±0.56 %ID/g）。
QQM 肽特异性结合 TEM8 的细胞外结构域。18F-FP-QQM 肽示踪剂将是测量 TEM8 表达的有前途的先导化合物。进一步努力提高示踪剂的亲和力和特异性，并增加其代谢稳定性是必要的。
