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Terbium-161 for PSMA-targeted radionuclide therapy of prostate cancer

Journal article
Authors C. Muller
C. A. Umbricht
N. Gracheva
V. J. Tschan
G. Pellegrini
Peter Bernhardt
J. R. Zeevaart
U. Koster
R. Schibli
N. P. van der Meulen
Published in European Journal of Nuclear Medicine and Molecular Imaging
Volume 46
Issue 9
Pages 1919-1930
ISSN 1619-7070
Publication year 2019
Published at Institute of Clinical Sciences, Department of Radiation Physics
Pages 1919-1930
Language en
Links dx.doi.org/10.1007/s00259-019-04345...
Keywords Tb-161, Auger electrons, Prostate cancer, PSMA ligands, Radioligand therapy, membrane antigen-expression, radioligand therapy, lu-177, ligands, dosimetry, diagnosis, toxicity, in-111, assay, pet, Radiology, Nuclear Medicine & Medical Imaging
Subject categories Physical Sciences

Abstract

PurposeThe prostate-specific membrane antigen (PSMA) has emerged as an interesting target for radionuclide therapy of metastasized castration-resistant prostate cancer (mCRPC). The aim of this study was to investigate Tb-161 (T-1/2=6.89days; E beta(?)(av)=154keV) in combination with PSMA-617 as a potentially more effective therapeutic alternative to Lu-177-PSMA-617, due to the abundant co-emission of conversion and Auger electrons, resulting in an improved absorbed dose profile.Methods(161)Tb was used for the radiolabeling of PSMA-617 at high specific activities up to 100MBq/nmol. Tb-161-PSMA-617 was tested in vitro and in tumor-bearing mice to confirm equal properties, as previously determined for Lu-177-PSMA-617. The effects of Tb-161-PSMA-617 and Lu-177-PSMA-617 on cell viability (MTT assay) and survival (clonogenic assay) were compared in vitro using PSMA-positive PC-3 PIP tumor cells. Tb-161-PSMA-617 was further investigated in therapy studies using PC-3 PIP tumor-bearing mice.Results(161)Tb-PSMA-617 and Lu-177-PSMA-617 displayed equal in-vitro properties and tissue distribution profiles in tumor-bearing mice. The viability and survival of PC-3 PIP tumor cells were more reduced when exposed to Tb-161-PSMA-617 as compared to the effect obtained with the same activities of Lu-177-PSMA-617 over the whole investigated concentration range. Treatment of mice with Tb-161-PSMA-617 (5.0MBq/mouse and 10MBq/mouse, respectively) resulted in an activity-dependent increase of the median survival (36 vs 65days) compared to untreated control animals (19days). Therapy studies to compare the effects of Tb-161-PSMA-617 and Lu-177-PSMA-617 indicated the anticipated superiority of Tb-161 over Lu-177.Conclusion(161)Tb-PSMA-617 showed superior in-vitro and in-vivo results as compared to Lu-177-PSMA-617, confirming theoretical dose calculations that indicate an additive therapeutic effect of conversion and Auger electrons in the case of Tb-161. These data warrant more preclinical research for in-depth investigations of the proposed concept, and present a basis for future clinical translation of Tb-161-PSMA-617 for the treatment of mCRPC.

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