Abstract
PurposeThe 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).MethodsThe 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.ResultsIn 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.ConclusionThe 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.
Highlights
Neuroendocrine neoplasms (NENs) are clinically heterogeneous malignancies, which originate in the neuroendocrine system mostly in the gastro-pancreatic or bronchopulmonary tract [1]
DOTA-LM3, irrespective of whether it was labeled with terbium-161 or lutetium-177 [43], showed the highest AR42J tumor cell uptake in vitro with ~70% of total added activity after a 2-h incubation period. This was 4- to sixfold higher than the uptake of radiolabeled DOTATOC (~ 10%) and DOTATOC-nuclear localizing sequence (NLS) (~ 15%), respectively (Fig. 1a–c); (Supplementary Material, Fig. S3)
In all cases, the 161Tb-labeled SST analogue was more potent in reducing AR42J tumor cell viability than the 177Lu-labeled analogue (Fig. 2a–c, Table S1, Supplementary Material). [161Tb]Tb-DOTATOC and [ 161Tb] Tb-DOTATOC-NLS were ~ 5- and ~ fourfold more potent than [177Lu]Lu-DOTATOC and [177Lu]Lu-DOTATOC-NLS, respectively, but [161Tb]Tb-DOTA-LM3 was 102-fold more potent than [177Lu]Lu-DOTA-LM3
Summary
Neuroendocrine neoplasms (NENs) are clinically heterogeneous malignancies, which originate in the neuroendocrine system mostly in the gastro-pancreatic or bronchopulmonary tract [1]. Peptide receptor radionuclide therapy (PRRT) using radiolabeled somatostatin (SST) analogues has been employed since the early 1990s to treat somatostatin receptor (SSTR)-positive NENs [1, 2]. The application of yttrium-90 was introduced in the late 1990s using the next-generation SSTR agonists, DOTATOC and DOTATATE [6, 7]. Yttrium-90 was more successfully used for PRRT; the high energy β-particles Tissue range: ~ 2 mm [9]) has a more favorable safety profile [8] and is currently the most often employed radiometal for PRRT using DOTATATE (LutatheraTM) or DOTATOC [10, 11]. The emission of γ-rays makes lutetium-177 useful for γ-scintigraphy and single photon emission computed tomography (SPECT) enabling therapy monitoring and dosimetry [12]
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