68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology
68Ga/177Lu-NeoBOMB1, a Novel Radiolabeled GRPR Antagonist for Theranostic Use in Oncology
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DOI：
10.2967/jnumed.116.176636
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发表时间：
2017-02-01
影响因子：
9.3
通讯作者：
de Jong, Marion
中科院分区：
文献类型：
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作者：
Dalm, Simone U.;Bakker, Ingrid L.;de Jong, Marion
由于已报道胃泌素释放肽受体 (GRPR) 在多种癌症类型中过度表达，例如前列腺癌和乳腺癌，因此用放射性配体靶向该受体可能对表达 GRPR 的肿瘤的分期和治疗产生重大影响。 NeoBOMB1是一种新型的DOTA偶联GRPR拮抗剂，对GRPR具有高亲和力和优异的体内稳定性。本临床前研究的目的是通过确定 Ga-68-NeoBOMB1 和 Lu-177-NeoBOMB1 的生物分布，进一步探索 NeoBOMB1 在治疗诊断中的应用。方法：向 PC-3 肿瘤异种移植的 BALB/c nu/nu 小鼠注射约 13 MBq/250 pmol Ga-68-NeoBOMB1 或低量（类似于 1 MBq/200 pmol）与高量（类似于 1 MBq/10 pmol）的 Lu-177-NeoBOMB1 肽，然后进行生物分布和成像研究。在 6 个时间点（Ga-68-NeoBOMB1 为 15、30、60、120、240 和 360 分钟，Lu-177-NeoBOMB1 为 1、4、24、48、96 和 168 小时）测定注射后肿瘤和器官的摄取。为了评估受体特异性，另外几组动物同时注射了过量的未标记 NeoBOMB1。生物分布研究的结果用于确定药代动力学和剂量测定。此外，还进行了 PET/CT 和 SPECT/MRI。结果：注射约 250 pmol Ga-68-NeoBOMB1 导致肿瘤和胰腺在注射后 120 分钟分别摄取每克组织 12.4 +/- 2.3 和 22.7 +/- 3.3 注射剂量百分比 (%ID/g)。 Lu-177-NeoBOMB1 生物分布研究显示，注射的肽量较高时，肿瘤摄取量较高（注射后 240 分钟时，肿瘤摄取量为 17.9 +/- 3.3 与 11.6 +/- 1.3 %ID/g 组织），而胰腺摄取量较低（注射后 240 分钟时，胰腺摄取量为 19.8 +/- 6.9 与 105 13 %ID/g 组织），从而导致肿瘤与胰腺的吸收剂量（200 pmol，570 vs. 265 mGy/MBq；10 pmol，435 vs. 1393 mGy/MBq）。使用这些数据来预测患者剂量测定，我们发现肾脏、胰腺和肝脏的暴露量分别为 0.10、0.65 和 0.06 mGy/MBq。 Ga-68-NeoBOMB1 和 Lu-177-NeoBOMB1 的影像学研究使肿瘤得到良好的可视化。结论：我们的研究结果表明，Ga-68 或 Lu-177 标记的 NeoBOMB1 是一种有前途的放射性示踪剂，具有良好的肿瘤摄取性和良好的药代动力学，适用于表达 GRPR 的肿瘤的成像和治疗。
Because overexpression of the gastrin-releasing peptide receptor (GRPR) has been reported on various cancer types, for example, prostate cancer and breast cancer, targeting this receptor with radioligands might have a significant impact on staging and treatment of GRPR-expressing tumors. NeoBOMB1 is a novel DOTA-coupled GRPR antagonist with high affinity for GRPR and excellent in vivo stability. The purpose of this preclinical study was to further explore the use of NeoBOMB1 for theranostic application by determining the biodistribution of Ga-68-NeoBOMB1 and Lu-177-NeoBOMB1. Methods: PC-3 tumor-xenografted BALB/c nu/nu mice were injected with either approximately 13 MBq/250 pmol Ga-68-NeoBOMB1 or a low (similar to 1 MBq/200 pmol) versus high (similar to 1 MBq/10 pmol) peptide amount of Lu-177-NeoBOMB1, after which biodistribution and imaging studies were performed. At 6 time points (15, 30, 60, 120, 240, and 360 min for Ga-68-NeoBOMB1 and 1, 4, 24, 48, 96, and 168 h for Lu-177-NeoBOMB1) postinjection tumor and organ uptake was determined. To assess receptor specificity, additional groups of animals were coinjected with an excess of unlabeled NeoBOMB1. Results of the biodistribution studies were used to determine pharmacokinetics and dosimetry. Furthermore, PET/CT and SPECT/MRI were performed. Results: Injection of approximately 250 pmol Ga-68-NeoBOMB1 resulted in a tumor and pancreas uptake of 12.4 +/- 2.3 and 22.7 +/- 3.3 percentage injected dose per gram (%ID/g) of tissue, respectively, at 120 min after injection. Lu-177-NeoBOMB1 biodistribution studies revealed a higher tumor uptake (17.9 +/- 3.3 vs. 11.6 +/- 1.3 %ID/g of tissue at 240 min after injection) and a lower pancreatic uptake (19.8 +/- 6.9 vs. 105 13 %ID/g of tissue at 240 min after injection) with the higher peptide amount injected, leading to a significant increase in the absorbed dose to the tumor versus the pancreas (200 pmol, 570 vs. 265 mGy/MBq; 10 pmol, 435 vs. 1393 mGy/MBq). Using these data to predict patient dosimetry, we found a kidney, pancreas, and liver exposure of 0.10, 0.65, and 0.06 mGy/MBq, respectively. Imaging studies resulted in good visualization of the tumor with both Ga-68-NeoBOMB1 and Lu-177-NeoBOMB1. Conclusion: Our findings indicate that Ga-68- or Lu-177-labeled NeoBOMB1 is a promising radiotracer with excellent tumor uptake and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.