In vitro dose effect relationships of actinium-225- and lutetium-177-labeled PSMA-I&T

Eline A.M. Ruigrok, Giulia Tamborino, Erik de Blois, Stefan J. Roobol, Nicole Verkaik, Marijke De Saint-Hubert, Mark W. Konijnenberg, Wytske M. van Weerden, Marion de Jong, Julie Nonnekens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)
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Abstract

Purpose: Targeting the prostate-specific membrane antigen (PSMA) using lutetium-177-labeled PSMA-specific tracers has become a very promising novel therapy option for prostate cancer (PCa). The efficacy of this therapy might be further improved by replacing the β-emitting lutetium-177 with the α-emitting actinium-225. Actinium-225 is thought to have a higher therapeutic efficacy due to the high linear energy transfer (LET) of the emitted α-particles, which can increase the amount and complexity of the therapy induced DNA double strand breaks (DSBs). Here we evaluated the relative biological effectiveness of [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T by assessing in vitro binding characteristics, dosimetry, and therapeutic efficacy. Methods and results: The PSMA-expressing PCa cell line PC3-PIP was used for all in vitro assays. First, binding and displacement assays were performed, which revealed similar binding characteristics between [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T. Next, the assessment of the number of 53BP1 foci, a marker for the number of DNA double strand breaks (DSBs), showed that cells treated with [225Ac]Ac-PSMA-I&T had slower DSB repair kinetics compared to cells treated with [177Lu]Lu-PSMA-I&T. Additionally, clonogenic survival assays showed that specific targeting with [225Ac]Ac-PSMA-I&T and [177Lu]Lu-PSMA-I&T caused a dose-dependent decrease in survival. Lastly, after dosimetric assessment, the relative biological effectiveness (RBE) of [225Ac]Ac-PSMA-I&T was found to be 4.2 times higher compared to [177Lu]Lu-PSMA-I&T. Conclusion: We found that labeling of PSMA-I&T with lutetium-177 or actinium-225 resulted in similar in vitro binding characteristics, indicating that the distinct biological effects observed in this study are not caused by a difference in uptake of the two tracers. The slower repair kinetics of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T correlates to the assumption that irradiation with actinium-225 causes more complex, more difficult to repair DSBs compared to lutetium-177 irradiation. Furthermore, the higher RBE of [225Ac]Ac-PSMA-I&T compared to [177Lu]Lu-PSMA-I&T underlines the therapeutic potential for the treatment of PCa.

Original languageEnglish
Pages (from-to)3627-3638
Number of pages12
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Volume49
Issue number11
Early online date12 May 2022
DOIs
Publication statusPublished - Sept 2022

Bibliographical note

Funding Information:
In memory of our beloved Professor Marion de Jong, who we miss dearly. Marion passed away during preparation of the manuscript. She was involved in the financing, development, and main supervision of the project. We are grateful to the radiochemistry group of the Dept. of Radiology and Nuclear Medicine of the Erasmus MC, who provided radiolabeled PSMA-I&T. Fluorescent imaging was performed in collaboration with the Optical Imaging Center core facility. The PC3-PIP cells were kindly provided by Professor Anna Orlova, Uppsala University.

Funding Information:
This work was supported by the Dutch Cancer Society (KWF; grant 10317).

Publisher Copyright:
© 2022, The Author(s).

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