Combination of Terbium-161 with Somatostatin Receptor Antagonists-a Potential Paradigm Shift for the Treatment of Neuroendocrine Neoplasms

Overview

Journal Eur J Nucl Med Mol Imaging

Specialties Biophysics
Nuclear Medicine
Radiology

Date 2021 Oct 9

PMID 34625828

Citations 28

Authors

Francesca Borgna

Stephanie Haller

Josep M Monne Rodriguez

Mihaela Ginj

Pascal V Grundler

Jan Rijn Zeevaart

Ulli Koster

Roger Schibli

Nicholas P van der Meulen

Cristina Muller

Affiliations

Soon will be listed here.

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.

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