Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
Chemical and Synthesis Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland.
J Nucl Med. 2023 Apr;64(4):549-554. doi: 10.2967/jnumed.122.264707. Epub 2022 Nov 17.
Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with Lu-DOTATATE (DOTA-octreotate), a β-particle-emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with Lu-DOTATATE-resistant disease. Although DOTATATE can chelate the clinically relevant α-particle-emitting radionuclide Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating Ac at room temperature, and assessed its in vitro and in vivo performance. MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of Ac-MACROPATATE than of Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with Ac-DOTATATE. Ac-MACROPATATE and Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of Ac-MACROPATATE, Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.
神经内分泌肿瘤 (NETs) 表达生长抑素受体 (SSTRs) 2 和 5。作为 SSTR2 和 SSTR5 的配体，生长抑素的修饰变体，被用于治疗转移性和局部疾病。用 Lu-DOTATATE（DOTA-奥曲肽）进行肽受体放射性核素治疗，这是一种β粒子发射的生长抑素衍生物，已在 SSTR 阳性 NETs 患者中显示出生存获益。尽管取得了优异的结果，但仍有一部分患者的肿瘤对治疗有抗药性，需要替代药物。靶向α粒子治疗已被证明可以杀死对靶向β粒子治疗有抗药性的肿瘤，这表明靶向α粒子治疗可能为 Lu-DOTATATE 耐药疾病的患者提供一种有前途的治疗选择。虽然 DOTATATE 可以螯合临床相关的α粒子发射放射性核素 Ac，但标记反应需要高温，并且所得放射性缀合物的稳定性不理想。我们设计并合成了 MACROPATATE（MACROPA-奥曲肽），这是一种能够在室温下螯合 Ac 的新型放射性缀合物，并评估了其体外和体内性能。MACROPATATE 在 U2-OS-SSTR2 中与 DOTATATE 具有相当的亲和力（解离常数，21 nM），U2-OS-SSTR2 是一种 SSTR2 阳性转染细胞系。与 Ac-DOTATATE 相比，Ac-MACROPATATE 在 37°C 下随时间的血清稳定性更高。生物分布研究表明，在皮下植入 H69 NETs 的小鼠中，Ac-MACROPATATE 的肿瘤摄取量高于 Ac-DOTATATE。治疗研究表明，与盐水对照相比，在植入 SSTR 阳性肿瘤的小鼠中，Ac-MACROPATATE 具有显著的抗肿瘤和生存获益。然而，与 Ac-DOTATATE 相比，Ac-MACROPATATE 在肝脏和肾脏中的积累增加以及随后对这些器官的毒性降低了其治疗指数。Ac-MACROPATATE 和 Ac-DOTATATE 在动物模型中表现出良好的治疗效果。由于 Ac-MACROPATATE 的肝脏和肾脏积累增加以及剂量限制毒性的给药活性降低，因此认为 Ac-DOTATATE 是用于靶向α粒子肽受体放射性核素治疗的更优药物。
