Extensive preclinical evaluation of lutetium-177-labeled PSMA-specific tracers for prostate cancer radionuclide therapy

Eline A.M. Ruigrok, Nicole van Vliet, Simone U. Dalm, Erik de Blois, Dik C. van Gent, Joost Haeck, Corrina de Ridder, Debra Stuurman, Mark W. Konijnenberg, Wytske M. van Weerden, Marion de Jong, Julie Nonnekens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

37 Citations (Scopus)
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Purpose: Various radiolabeled prostate-specific membrane antigen (PSMA)–targeting tracers are clinically applied for prostate cancer (PCa) imaging and targeted radionuclide therapy. The PSMA binding affinities, biodistribution, and DNA-damaging capacities of these radiotracers have not yet been compared in detail. A major concern of PSMA-targeting radiotracers is the toxicity in other PSMA-expressing organs, such as the salivary glands, thus demanding careful evaluation of the most optimal and safest radiotracer. In this extensive preclinical study, we evaluated the clinically applied PSMA-targeting small molecule inhibitors DOTA-PSMA-617 (PSMA-617) and DOTAGA-PSMA-I&T (PSMA-I&T) and the PSMA nanobody DOTA-JVZ-007 (JVZ-007) using PSMA-expressing cell lines, a unique set of PCa patient-derived xenografts (PDX) and healthy human tissues. Methods and results: In vitro displacement studies on PSMA-expressing cells and cryosections of a PSMA-positive PDX revealed high and specific binding affinity for all three tracers labeled with lutetium-177 with IC50 values in the nanomolar range. Interestingly, [177Lu]Lu-JVZ-007 could not be displaced by PSMA-617 or PSMA-I&T, suggesting that this tracer targets an alternative binding site. Autoradiography assays on cryosections of human salivary and renal tissues revealed [177Lu]Lu-PSMA-617 to have the lowest binding to these healthy organs compared with [177Lu]Lu-PSMA-I&T. In vivo biodistribution assays confirmed the in vitro results with comparable tumor uptake of [177Lu]Lu-PSMA-617 and [177Lu]Lu-PSMA-I&T at all timepoints, resulting in induction of similar levels of DNA double-strand breaks in the tumors. However, [177Lu]Lu-PSMA-I&T demonstrated approximately 40× higher renal uptake at 4 and 8 h post injection resulting in an unfavorable tumor-to-kidney ratio. Conclusion: [177Lu]Lu-PSMA-617 has the most favorable biodistribution in mice as well as more favorable binding characteristics in vitro in PSMA-positive cells and human kidney and salivary gland specimens compared with [177Lu]Lu-PSMA-I&T and [177Lu]Lu-JVZ-007. Based on our preclinical evaluation, [177Lu]Lu-PSMA-617 is the best performing tracer to be taken further into clinical evaluation for PSMA-targeted radiotherapeutic development although with careful evaluation of the tracer binding to PSMA-expressing organs.

Original languageEnglish
Pages (from-to)1339-1350
Number of pages12
JournalEuropean Journal of Nuclear Medicine and Molecular Imaging
Issue number5
Early online date23 Oct 2020
Publication statusPublished - May 2021

Bibliographical note

Funding Information:
Open access funding provided by University Medical Center Rotterdam (Erasmus MC). This work was supported by the Dutch Cancer Society (KWF; grant 10317). Acknowledgments

Funding Information:
We would like to thank Wenhao Zhang for his help in making the PSMA-expressing DU145 and U2OS cell lines. We would like to thank Stefan Roobol and Danny Feijtel for their help during the DNA damage foci quantifications. Fluorescent imaging was performed in collaboration with the Optical Imaging Center core facility (OIC) and animal imaging experiments in collaboration with the Applied Molecular Imaging core facility (AMIE) of the Erasmus MC.

Publisher Copyright:
© 2020, The Author(s).


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