Ingham Aidan, Wharton Luke, Koniar Helena, Merkens Helen, McNeil Scott, Sekar Sathiya, Osooly Maryam, Rodríguez-Rodríguez Cristina, Bénard François, Schaffer Paul, Yang Hua
Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada.
Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, British Columbia V6T 2A3, Canada; Department of Physics and Astronomy, University of British Columbia, 6224 Agronomy Road, Vancouver, British Columbia V6T 1Z1, Canada.
Nucl Med Biol. 2024 Nov-Dec;138-139:108944. doi: 10.1016/j.nucmedbio.2024.108944. Epub 2024 Jul 31.
Targeted alpha therapy (TAT) of somatostatin receptor-2 (SSTR2) positive neuroendocrine tumors (NETs) involving Ac-225 ([Ac]Ac-DOTA-TATE) has previously demonstrated improved therapeutic efficacy over conventional beta particle-emitting peptide receptor radionuclide therapy agents. DOTA-TATE requires harsh radiolabeling conditions for chelation of [Ac]Ac, which can limit the achievable molar activities and thus therapeutic efficacy of such TAT treatments. Macropa-TATE was recently highlighted as a potential alternative to DOTA-TATE, owing to the mild radiolabeling conditions and high affinity toward [Ac]Ac; however, elevated liver and kidney uptake were noted as a major limitation and a suitable imaging radionuclide is yet to be reported, which will be required for patient dosimetry studies and assessment of therapeutic benefit. Previously, [Tb]Tb-crown-TATE has shown highly effective imaging of NETs in preclinical SPECT/CT studies, with high tumor uptake and low non-target accumulation; these favourable properties and the versatile coordination behavior of the crown chelator may therefore show promise for combination with Ac-225 for TAT.
Crown-TATE was labeled with Ac-225, and radiochemical yield was analyzed as the function of crown-TATE concentration. LogD was measured as the indication of hydrophilicity. Free [Ac]Ac release from [Ac]Ac-crown-TATE in human serum was studied. Biodistribution studies of [Ac]Ac-crown-TATE in mice bearing AR42J tumors was evaluated at 1, 4, 24, 48, and 120 h, and the absorbed dose to major organs calculated. Therapy-monitoring studies with AR42J tumor bearing mice were undertaken using 30 kBq and 55 kBq doses of [Ac]Ac-crown-TATE and compared to controls treated with PBS or crown-TATE.
[Ac]Ac-crown-TATE was successfully prepared with high molar activity (640 kBq/nmol), and characterized as a moderately hydrophilic radioligand (LogD = -1.355 ± 0.135). No release of bound Ac-225 was observed over 9 days in human serum. Biodistribution studies of [Ac]Ac-crown-TATE showed good initial tumor uptake (11.1 ± 1.7% IA/g at 4 h) which was sustained up to 120 h p.i. (6.92 ± 2.03% IA/g). Dosimetry calculations showed the highest absorbed dose was delivered to the tumors. Therapy monitoring studies demonstrated significant (log-rank test, P < 0.005) improved survival in both treatment groups compared to controls.
This preclinical study demonstrated the therapeutic efficacy of [Ac]Ac-crown-TATE for treatment of NETs, and highlights the potential of using crown chelator for stable chelation of Ac-225 under mild conditions.
靶向α疗法（TAT）用于治疗生长抑素受体2（SSTR2）阳性神经内分泌肿瘤（NETs），所涉及的锕-225（[Ac]Ac-DOTA-TATE）相较于传统的发射β粒子的肽受体放射性核素治疗药物，已显示出更高的治疗效果。DOTA-TATE需要苛刻的放射性标记条件来螯合[Ac]Ac，这可能会限制可达到的摩尔活度，从而限制此类TAT治疗的疗效。Macropa-TATE由于其温和的放射性标记条件以及对[Ac]Ac的高亲和力，最近被视为DOTA-TATE的潜在替代品；然而，肝脏和肾脏摄取增加被视为一个主要限制因素，且尚未有适用于患者剂量测定研究和治疗益处评估的合适成像放射性核素的报道。此前，[Tb]Tb-冠醚-TATE在临床前SPECT/CT研究中已显示出对NETs的高效成像，具有高肿瘤摄取和低非靶器官蓄积；因此，这些有利特性以及冠醚螯合剂的多功能配位行为可能有望与锕-225联合用于TAT。
用锕-225标记冠醚-TATE，并分析放射化学产率与冠醚-TATE浓度的函数关系。测量LogD以指示亲水性。研究了[Ac]Ac-冠醚-TATE在人血清中游离[Ac]Ac的释放情况。在荷AR42J肿瘤小鼠中于1、4、24、48和120小时评估[Ac]Ac-冠醚-TATE的生物分布研究，并计算主要器官的吸收剂量。对荷AR42J肿瘤小鼠进行治疗监测研究，使用30 kBq和55 kBq剂量的[Ac]Ac-冠醚-TATE，并与用PBS或冠醚-TATE治疗的对照组进行比较。
成功制备了具有高摩尔活度（640 kBq/nmol）的[Ac]Ac-冠醚-TATE，并将其表征为中等亲水性放射性配体（LogD = -1.355 ± 0.135）。在人血清中9天内未观察到结合的锕-225释放。[Ac]Ac-冠醚-TATE的生物分布研究显示，初始肿瘤摄取良好（4小时时为11.1 ± 1.7% IA/g），直至注射后120小时仍保持（6.92 ± 2.03% IA/g）。剂量测定计算表明，肿瘤接受的吸收剂量最高。治疗监测研究表明，与对照组相比，两个治疗组的生存率均有显著提高（对数秩检验，P < 0.005）。
这项临床前研究证明了[Ac]Ac-冠醚-TATE治疗NETs的疗效，并突出了在温和条件下使用冠醚螯合剂稳定螯合锕-225的潜力。
