Small-animal PET Imaging of human epidermal growth factor receptor type 2 expression with site-specific 18F-labeled protein scaffold molecules
Small-animal PET Imaging of human epidermal growth factor receptor type 2 expression with site-specific 18F-labeled protein scaffold molecules
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DOI：
10.2967/jnumed.107.047381
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发表时间：
2008-05-01
影响因子：
9.3
通讯作者：
Gambhir, Sanjiv Sam
中科院分区：
文献类型：
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作者：
Cheng, Zhen;De Jesus, Omayra Padilla;Gambhir, Sanjiv Sam
人表皮生长因子受体2(HER2)是一种公认的肿瘤生物标志物，在多种癌症中过度表达，并作为治疗干预的分子靶点。HER2也可作为患者生存的预后指标和抗肿瘤治疗反应的预测指标。F-18标记的HER2生物分子的研制对HER2的PET成像具有重要意义，因为它可能为HER2阳性肿瘤复发的早期发现和HER2肿瘤治疗的监测提供有力的工具。方法：在本研究中，抗HER2单体和二聚体蛋白支架分子[Z(HER2：477)和Z(HER2：477))(2)]分别以合理的放射化学产率(13%-18%)被放射氟化。然后，通过SKOV3荷瘤小鼠模型，将得到的放射性氟化蛋白支架分子作为潜在的小动物HER2 PET的分子探针进行评估。结果：4-F-18-氟苯甲醛偶联氨基氧基蛋白质支架[F-18-N-(4-氟苯亚甲基)肟(FBO)-Z(HER2：477)]和F-18-FBO-(Z(HER2：477))(2)在体外均具有与HER2特异的结合能力。生物分布和小动物PET成像研究进一步表明，F-18-FBO-Z(HER2：477)表现出快速而高的SKOV3肿瘤聚集和正常组织的快速清除，而F-18-FBO-(Z(HER2：477))(2)在体内表现较差(低肿瘤摄取率和肿瘤与正常组织的比率)。F-18-FBO-Z(HER2：477)对荷瘤小鼠对HER2靶向剂ZHER2和曲妥珠单抗的摄取较低，证实了其对SKOV3肿瘤的特异性。此外，小动物PET成像研究表明，F-18-FBO-Z(HER2：477)比F-18-FBO-(Z(HER2：477))(2)产生更高质量的肿瘤成像。F-18-FBO-Z(HER2：477)能清晰识别HER2阳性肿瘤，对比度好。结论：总体而言，这些数据表明F-18-FBO-Z(HER2：477)是一种有希望的用于活体小鼠HER2表达的PET探针。它具有很高的转化为临床应用的潜力。所开发的放射性氟化方法也可用作F-18对其他蛋白质进行位置特异性标记的一般策略。本文所使用的蛋白质支架分子对进一步开发用于其他分子靶点的PET探针具有很大的吸引力。
Human epidermal growth factor receptor type 2 (HER2) is a well-established tumor biomarker that is overexpressed in a wide variety of cancers and that serves as a molecular target for therapeutic intervention. HER2 also serves as a prognostic indicator of patient survival and as a predictive marker of the response to antineoplastic therapy. The development of F-18-labeled biomolecules for PET imaging of HER2 (HER2 PET) is very important because it may provide a powerful tool for the early detection of HER2-positive tumor recurrence and for the monitoring of HER2-based tumor treatment. Methods: In this study, anti-HER2 monomeric and dimeric protein scaffold molecules [Z(HER2:477) and (Z(HER2:477))(2), respectively] were radiofluorinated at a reasonable radiochemical yield (13%-18%) by use of site-specific oxime chemistry. The resulting radiofluorinated protein scaffold molecules were then evaluated as potential molecular probes for small-animal HER2 PET by use of a SKOV3 tumor-bearing mouse model. Results: The 4-F-18-fluorobenzaldehyde conjugated aminooxy-protein scaffolds [F-18-N-(4-fluorobenzylidene)oxime (FBO)-Z(HER2:477) and F-18-FBO-(Z(HER2:477))(2)] both displayed specific HER2-binding ability in vitro. Biodistribution and small-animal PET imaging studies further revealed that F-18-FBO-Z(HER2:477) showed rapid and high SKOV3 tumor accumulation and quick clearance from normal tissues, whereas F-18-FBO-(Z(HER2:477))(2) showed poor in vivo performance (low tumor uptake and tumor-to-normal tissue ratios). The specificity of F-18-FBO-Z(HER2:477) for SKOV3 tumors was confirmed by its lower uptake on pretreatment of tumor-bearing mice with the HER2-targeting agents ZHER2 and trastuzumab. Moreover, small-animal PET imaging studies revealed that F-18-FBO-Z(HER2:477) produced higher-quality tumor imaging than F-18-FBO-(Z(HER2:477))(2). F-18-FBO-Z(HER2:477) could clearly identify HER2-positive tumors with good contrast. Conclusion: Overall, these data demonstrate that F-18-FBO-Z(HER2:477) is a promising PET probe for imaging HER2 expression in living mice. It has a high potential for translation to clinical applications. The radiofluorination method developed can also be used as a general strategy for the site-specific labeling of other proteins with F-18. The protein scaffold molecules used here are attractive for the further development of PET probes for other molecular targets.