Holzleitner Nadine, Vilangattil Meryl, Swaidan Abir, Garcia-Prada Clara Diaz, Taddio Marco F, Jeanjean Pauline, Mona Christine E, Lapa Constantin, Casini Angela, Günther Thomas, Carlucci Giuseppe
Chair of Pharmaceutical Radiochemistry, Department of Chemistry, School of Natural Sciences, Technical University of Munich, Walther-Meissner-Str. 3, 85748, Garching, Germany.
Department of Molecular and Medical Pharmacology, Biomedical Cyclotron Facility, University of California Los Angeles, 780 Westwood Plaza, Los Angeles, CA, 90024, USA.
Eur J Nucl Med Mol Imaging. 2025 Jan;52(2):458-468. doi: 10.1007/s00259-024-06927-z. Epub 2024 Oct 11.
The recently developed metabolically more stable minigastrin derivative, DOTA-CCK-66, displayed promising preclinical data when labeled either with Ga or Lu. First positron emission tomography/computed tomography (PET/CT) imaging using [Ga]Ga-DOTA-CCK-66 in two patients suffering from medullary thyroid carcinoma (MTC) displayed a favorable biodistribution profile. Here, we aim to investigate the therapeutic potential of [Ac]Ac-DOTA-CCK-66 as a targeted α-therapy (TAT) agent in a comparative treatment study of [Lu]Lu- versus [Ac]Ac-DOTA-CCK-66.
Treatment studies were performed (3 groups, n = 5, AR42J tumor-bearing 394-NOD SCID mice). Control group animals were injected with [Ga]Ga-DOTA-CCK-66 (1.1 MBq, PET/CT imaging), while treatment group animals received a single dose of either [Lu]Lu-DOTA-CCK-66 (37 MBq, radioligand therapy (RLT)) or [Ac]Ac-DOTA-CCK-66 (37 kBq, TAT). All animals' tumor volume and body weight were monitored twice a week until end-point criteria were reached. Blood samples were evaluated (VetScan VS2, Abaxis) once mice were sacrificed.
Upon treatment, an initial decline in tumor volume, followed by a significantly delayed tumor growth of treated cohorts, was observed. Mean survival of Lu- as well as Ac-treated animals was increased by 3- (37 ± 3 d) and 4.5-fold (54 ± 6 d), respectively, when compared to non-treated animals (12 ± 3 d). Blood sample analysis did not indicate toxic side effects to the liver, kidney, or stomach upon Lu and Ac-treatment.
We demonstrated a substantial therapeutic efficacy of Lu- and Ac-labeled DOTA-CCK-66. As expected, treatment with the latter resulted in the highest mean survival rates. These results indicate a high therapeutic potential of Ac-labeled DOTA-CCK-66 for TAT in MTC patient management.
最近开发的代谢更稳定的小胃泌素衍生物DOTA-CCK-66，用镓（Ga）或镥（Lu）标记时显示出有前景的临床前数据。在两名患有甲状腺髓样癌（MTC）的患者中使用[Ga]Ga-DOTA-CCK-66进行的首次正电子发射断层扫描/计算机断层扫描（PET/CT）成像显示出良好的生物分布特征。在此，我们旨在通过[Lu]Lu-DOTA-CCK-66与[Ac]Ac-DOTA-CCK-66的对比治疗研究，探讨[Ac]Ac-DOTA-CCK-66作为靶向α治疗（TAT）药物的治疗潜力。
进行治疗研究（3组，n = 5，携带AR42J肿瘤的394-NOD SCID小鼠）。对照组动物注射[Ga]Ga-DOTA-CCK-66（1. 1MBq，PET/CT成像），而治疗组动物接受单剂量的[Lu]Lu-DOTA-CCK-66（37MBq，放射性配体治疗（RLT））或[Ac]Ac-DOTA-CCK-66（37kBq，TAT）。每周监测所有动物的肿瘤体积和体重两次，直至达到终点标准。处死小鼠后评估血液样本（VetScan VS2，Abaxis）。
治疗后，观察到肿瘤体积最初下降，随后治疗组的肿瘤生长明显延迟。与未治疗的动物（12±3天）相比，用镥治疗和用锕治疗的动物的平均生存期分别延长了3倍（37±3天）和4.5倍（54±6天）。血液样本分析未表明用镥和锕治疗后对肝脏、肾脏或胃有有毒副作用。
我们证明了用镥和锕标记的DOTA-CCK-66具有显著的治疗效果。正如预期的那样，用后者治疗导致最高的平均生存率。这些结果表明，在MTC患者管理中，用锕标记的DOTA-CCK-66用于TAT具有很高的治疗潜力。
