PURPOSE The β¯-emitting terbium-161 also emits conversion and Auger electrons, which are believed to be effective in killing single cancer cells. Terbium-161 was applied with somatostatin receptor (SSTR) agonists that localize in the cytoplasm (DOTATOC) and cellular nucleus (DOTATOC-NLS) or with a SSTR antagonist that localizes at the cell membrane (DOTA-LM3). The aim was to identify the most favorable peptide/terbium-161 combination for the treatment of neuroendocrine neoplasms (NENs). METHODS The capability of the 161Tb- and 177Lu-labeled somatostatin (SST) analogues to reduce viability and survival of SSTR-positive AR42J tumor cells was investigated in vitro. The radiopeptides' tissue distribution profiles were assessed in tumor-bearing mice. The efficacy of terbium-161 compared to lutetium-177 was investigated in therapy studies in mice using DOTATOC or DOTA-LM3, respectively. RESULTS In vitro, [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3; however, 161Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their 177Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [161Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [177Lu]Lu-DOTA-LM3, thereby, prolonging survival of the mice. A therapeutic advantage of terbium-161 over lutetium-177 was also manifest when applied with DOTATOC. Since the nuclear localizing sequence (NLS) compromised the in vivo tissue distribution of DOTATOC-NLS, it was not used for therapy. CONCLUSION The use of membrane-localizing DOTA-LM3 was beneficial and profited from the short-ranged electrons emitted by terbium-161. Based on these preclinical data, [161Tb]Tb-DOTA-LM3 may outperform the clinically employed [177Lu]Lu-DOTATOC for the treatment of patients with NENs.

中文翻译：

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铽 161 与生长抑素受体拮抗剂的组合——治疗神经内分泌肿瘤的潜在范式转变。

目的 发射β¯的铽161还发射转换电子和俄歇电子，据信它们可有效杀死单个癌细胞。Terbium-161 与定位于细胞质 (DOTATOC) 和细胞核 (DOTATOC-NLS) 的生长抑素受体 (SSTR) 激动剂或定位于细胞膜的 SSTR 拮抗剂 (DOTA-LM3) 一起使用。目的是确定用于治疗神经内分泌肿瘤 (NEN) 的最有利的肽/铽 161 组合。方法 体外研究了 161Tb 和 177Lu 标记的生长抑素 (SST) 类似物降低 SSTR 阳性 AR42J 肿瘤细胞活力和存活率的能力。在荷瘤小鼠中评估了放射性肽的组织分布谱。在分别使用 DOTATOC 或 DOTA-LM3 对小鼠进行的治疗研究中，研究了 terbium-161 与 lutetium-177 的疗效。结果 在体外，[161Tb]Tb-DOTA-LM3 的效力是 [177Lu]Lu-DOTA-LM3 的 102 倍；然而，161Tb 标记的 DOTATOC 和 DOTATOC-NLS 对肿瘤细胞活力的抑制效果仅比 177Lu 标记的对应物高 4 到 5 倍。这一结果在体内得到证实，并证明 [161Tb]Tb-DOTA-LM3 在延缓肿瘤生长方面比 [177Lu]Lu-DOTA-LM3 显着更有效，从而延长了小鼠的存活时间。当与 DOTATOC 一起使用时，铽 161 相对于镥 177 的治疗优势也很明显。由于核定位序列 (NLS) 损害了 DOTATOC-NLS 的体内组织分布，因此未将其用于治疗。结论 使用膜定位 DOTA-LM3 是有益的，并且受益于 terbium-161 发射的短程电子。基于这些临床前数据，[161Tb]Tb-DOTA-LM3 在治疗 NEN 患者方面可能优于临床使用的 [177Lu]Lu-DOTATOC。