Department of Cancer Physiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Department of Radiology, University of Iowa Health Care, Iowa City, IA, USA.
Eur J Nucl Med Mol Imaging. 2021 Oct;48(11):3408-3421. doi: 10.1007/s00259-021-05315-1. Epub 2021 Mar 26.
There is significant interest in the development of targeted alpha-particle therapies (TATs) for treatment of solid tumors. The metal chelator-peptide conjugate, DOTA-TATE, loaded with the β-particle emitting radionuclide Lu ([Lu]Lu-DOTA-TATE) is now standard care for neuroendocrine tumors that express the somatostatin receptor 2 (SSTR2) target. A recent clinical study demonstrated efficacy of the corresponding [Ac]Ac-DOTA-TATE in patients that were refractory to [Lu]Lu-DOTA-TATE. Herein, we report the radiosynthesis, toxicity, biodistribution (BD), radiation dosimetry (RD), and efficacy of [Ac]Ac-DOTA-TATE in small animal models of lung neuroendocrine neoplasms (NENs).
[Ac]Ac-DOTA-TATE was synthesized and characterized for radiochemical yield, purity and stability. Non-tumor-bearing BALB/c mice were tested for toxicity and BD. Efficacy was determined by single intravenous injection of [Ac]Ac-DOTA-TATE into SCID mice-bearing human SSTR2 positive H727 and H69 lung NENs. RD was calculated using the BD data.
[Ac]Ac-DOTA-TATE was synthesized with 98% yield, 99.8% purity, and displayed 97% stability after 2 days incubation in human serum at 37 °C. All animals in the toxicity study appeared healthy 5 months post injection with no indications of toxicity, except that animals that received ≥111 kBq of [Ac]Ac-DOTA-TATE had chronic progressive nephropathy. BD studies revealed that the primary route of elimination is by the renal route. RD calculations determined pharmacokinetics parameters and absorbed α-emission dosages from Ac and its daughters. For both tumor models, a significant tumor growth delay and time to experimental endpoint were observed following a single administration of [Ac]Ac-DOTA-TATE relative to controls.
These results suggest significant potential for the clinical translation of [Ac]Ac-DOTA-TATE for lung NENs.
针对实体瘤的治疗，靶向α粒子疗法（TATs）的发展引起了广泛关注。金属螯合剂-肽缀合物 DOTA-TATE 与β粒子发射放射性核素 Lu（[Lu]Lu-DOTA-TATE）结合，现已成为表达生长抑素受体 2（SSTR2）靶标的神经内分泌肿瘤的标准治疗方法。最近的一项临床研究表明，相应的[Ac]Ac-DOTA-TATE 对[Lu]Lu-DOTA-TATE 耐药的患者有效。在此，我们报告了用于治疗肺神经内分泌肿瘤（NENs）的小动物模型的[Ac]Ac-DOTA-TATE 的放射合成、毒性、生物分布（BD）、辐射剂量学（RD）和疗效。
合成并表征了[Ac]Ac-DOTA-TATE 的放射化学产率、纯度和稳定性。非肿瘤荷瘤 BALB/c 小鼠进行毒性和 BD 检测。通过单次静脉注射[Ac]Ac-DOTA-TATE 至携带人 SSTR2 阳性 H727 和 H69 肺 NENs 的 SCID 小鼠，确定疗效。RD 是根据 BD 数据计算的。
[Ac]Ac-DOTA-TATE 的合成产率为 98%，纯度为 99.8%，在 37°C 下人血清中孵育 2 天后，稳定性为 97%。毒性研究中的所有动物在注射后 5 个月均表现健康，无毒性迹象，但接受≥111kBq [Ac]Ac-DOTA-TATE 的动物有慢性进行性肾病。BD 研究表明，主要的消除途径是通过肾脏途径。RD 计算确定了 Ac 及其子体的药代动力学参数和吸收的α发射剂量。对于两种肿瘤模型，与对照组相比，单次给予[Ac]Ac-DOTA-TATE 后，肿瘤生长明显延迟，实验终点时间延长。
这些结果表明，[Ac]Ac-DOTA-TATE 对肺 NENs 的临床转化具有重要潜力。
