Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer
Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer
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DOI：
10.1007/s00259-019-04345-0
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发表时间：
2019-08-01
影响因子：
9.1
通讯作者：
van der Meulen, Nicholas P.
中科院分区：
文献类型：
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作者：
Muller, Cristina;Umbricht, Christoph A.;van der Meulen, Nicholas P.
目的前列腺特异性膜抗原（PSMA）已成为转移性去势抵抗性前列腺癌（mCRPC）放射性核素治疗的一个有趣靶标。本研究的目的是研究 Tb-161 (T-1/2=6.89days; E beta(?)(av)=154keV) 与 PSMA-617 联合作为 Lu-177-PSMA-617 的潜在更有效的治疗替代品，由于转换和俄歇电子的丰富共发射，从而改善吸收剂量分布。方法(161)Tb 用于 PSMA-617 的放射性标记，比活度高达 100MBq/nmol。 Tb-161-PSMA-617 在体外和荷瘤小鼠中进行了测试，以确认与之前对 Lu-177-PSMA-617 测定的相同特性。使用 PSMA 阳性 PC-3 PIP 肿瘤细胞在体外比较 Tb-161-PSMA-617 和 Lu-177-PSMA-617 对细胞活力（MTT 测定）和存活（克隆形成测定）的影响。在使用 PC-3 PIP 荷瘤小鼠的治疗研究中进一步研究了 Tb-161-PSMA-617。结果(161)Tb-PSMA-617 和 Lu-177-PSMA-617 在荷瘤小鼠中显示出相同的体外特性和组织分布概况。在整个研究浓度范围内，与使用相同活性的 Lu-177-PSMA-617 获得的效果相比，当暴露于 Tb-161-PSMA-617 时，PC-3 PIP 肿瘤细胞的活力和存活率降低更多。与未治疗的对照动物（19天）相比，用Tb-161-PSMA-617（分别为5.0MBq/小鼠和10MBq/小鼠）治疗小鼠导致中位生存期的活动依赖性增加（36天与65天）。比较 Tb-161-PSMA-617 和 Lu-177-PSMA-617 效果的治疗研究表明 Tb-161 优于 Lu-177。结论(161)Tb-PSMA-617 与 Lu-177-PSMA-617 相比显示出更优异的体外和体内结果，证实了理论剂量计算表明添加剂 Tb-161 中转换电子和俄歇电子的治疗效果。这些数据需要更多的临床前研究来深入研究所提出的概念，并为 Tb-161-PSMA-617 治疗 mCRPC 的未来临床转化奠定基础。
PurposeThe prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate Tb-161 (T-1/2=6.89days; E beta(?)(av)=154keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to Lu-177-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.Methods(161)Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100MBq/nmol. Tb-161-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for Lu-177-PSMA-617. The effects of Tb-161-PSMA-617 and Lu-177-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. Tb-161-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.Results(161)Tb-PSMA-617 and Lu-177-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to Tb-161-PSMA-617 as compared to the effect obtained with the same activities of Lu-177-PSMA-617 over the whole investigated concentration range. Treatment of mice with Tb-161-PSMA-617 (5.0MBq/mouse and 10MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65days) compared to untreated control animals (19days). Therapy studies to compare the effects of Tb-161-PSMA-617 and Lu-177-PSMA-617 indicated the anticipated superiority of Tb-161 over Lu-177.Conclusion(161)Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to Lu-177-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of Tb-161. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of Tb-161-PSMA-617 for the treatment of mCRPC.