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镱-161 与生长抑素受体拮抗剂联合应用——神经内分泌肿瘤治疗的潜在范式转变。

Combination of terbium-161 with somatostatin receptor antagonists-a potential paradigm shift for the treatment of neuroendocrine neoplasms.

机构信息

Center for Radiopharmaceutical Sciences, ETH-PSI-USZ, Paul Scherrer Institute, 5232, Villigen-PSI, Switzerland.

Laboratory for Animal Model Pathology, Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, 8057, Zurich, Switzerland.

出版信息

Eur J Nucl Med Mol Imaging. 2022 Mar;49(4):1113-1126. doi: 10.1007/s00259-021-05564-0. Epub 2021 Oct 8.

DOI:10.1007/s00259-021-05564-0
PMID:34625828
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8921065/
Abstract

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 Tb- and Lu-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, [Tb]Tb-DOTA-LM3 was 102-fold more potent than [Lu]Lu-DOTA-LM3; however, Tb-labeled DOTATOC and DOTATOC-NLS were only 4- to fivefold more effective inhibiting tumor cell viability than their Lu-labeled counterparts. This result was confirmed in vivo and demonstrated that [Tb]Tb-DOTA-LM3 was significantly more effective in delaying tumor growth than [Lu]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, [Tb]Tb-DOTA-LM3 may outperform the clinically employed [Lu]Lu-DOTATOC for the treatment of patients with NENs.

摘要

目的

发射β射线的铽-161 还会发射转换电子和俄歇电子，据信这些电子在杀死单个癌细胞方面非常有效。铽-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）一起应用。目的是确定最适合用于治疗神经内分泌肿瘤（NENs）的肽/铽-161 组合。

方法

体外研究了 Tb 和 Lu 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。评估了放射性肽在荷瘤小鼠中的组织分布特征。在使用 DOTATOC 或 DOTA-LM3 的小鼠治疗研究中，分别研究了铽-161 与镥-177 的疗效。

结果

体外，[Tb]Tb-DOTA-LM3 比[Lu]Lu-DOTA-LM3 强 102 倍；然而，Tb 标记的 DOTATOC 和 DOTATOC-NLS 仅比其 Lu 标记的对应物抑制肿瘤细胞活力有效 4-5 倍。这一结果在体内得到了证实，并表明[Tb]Tb-DOTA-LM3 显著更有效地延迟肿瘤生长，从而延长了小鼠的存活时间。当应用 DOTATOC 时，铽-161 也显示出优于镥-177 的治疗优势。由于核定位序列（NLS）会影响 DOTATOC-NLS 的体内组织分布，因此未将其用于治疗。

结论

使用膜定位的 DOTA-LM3 是有益的，并受益于铽-161 发射的短程电子。基于这些临床前数据，[Tb]Tb-DOTA-LM3 可能优于临床应用的[Lu]Lu-DOTATOC，用于治疗 NENs 患者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/da45/8921065/c70b7a87802d/259_2021_5564_Fig7_HTML.jpg
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