Preclinical Evaluation of 226Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy.

Helena Koniar, Luke Wharton, Aidan Ingham, Ana Paulina Morales Oliver, Helen Merkens, Cristina Rodríguez-Rodríguez, Peter Kunz, Valery Radchenko, Hua Yang, Arman Rahmim, Carlos Uribe, Paul Schaffer
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Abstract

226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods: 226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals.

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226Ac 作为放射治疗剂的临床前评估:成像、剂量测定和治疗。
226Ac(t½ = 29.37 h)被提议作为一种治疗放射性同位素,利用其诊断性γ发射和治疗性α发射。226Ac 能发射 158 和 230 千伏的 γ 光子,是定量 SPECT 成像的理想选择,并能在体内产生 4 个高能 α 粒子。由于这些核衰变特性,226Ac 有可能成为一种独立的治疗同位素。在这项概念验证研究中,我们对一种临床前 226Ac 放射性药物的治疗效果进行了评估,并首次提出了 226Ac 靶向 α 治疗研究。方法:在 TRIUMF 生产 226Ac,并用螯合剂-肽生物共轭物 crown-TATE 进行标记。选择[226Ac]Ac-crown-TATE靶向携带AR42J肿瘤异种移植的雄性NRG小鼠的神经内分泌肿瘤,进行SPECT成像、生物分布和治疗研究。临床前 SPECT/CT 扫描仪可获得由 158 和 230 keV 发射重建的定量图像。生物分布研究中的小鼠在注射后 1、3、5、24 和 48 小时安乐死,并对肿瘤和相关器官进行内部辐射剂量测定,以确定适当的治疗活性水平。治疗研究中的小鼠分别接受了 125、250 或 375 kBq 的治疗,并对肿瘤大小和身体状况进行了监测。结果:我们展示了[226Ac]Ac-冠-TATE体内生物分布的定量SPECT图像,结果与体内外测量结果一致。生物分布研究表明,[226Ac]Ac-crown-TATE 在肿瘤中的吸收率很高(注射后 5 小时>30%IA/g),并在肿瘤中保留,估计平均吸收剂量系数为 222 mGy/kBq。[226Ac]Ac-冠-TATE治疗可显著延长中位生存期,从对照组的7天分别延长到125、250和375 kBq治疗组的16、24和27天。生存期的延长是通过减缓肿瘤生长来实现的,而且没有观察到体重减轻或毒性反应。结论这项研究强调了 226Ac 作为独立治疗同位素的治疗潜力,以及它在评估匹配的 225Ac 放射药物剂量学方面的诊断能力。未来的研究将调查最大剂量和毒性,以进一步探索 226Ac 放射药品的治疗潜力。
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