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A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals

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Abstract

Purpose

Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [177Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [177Lu]-PSMA-617 and other small molecule–based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [177Lu]-PSMA-617 in the salivary glands and kidneys.

Methods

Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [177Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h.

Results

Biodistribution studies at 1 h post-administration revealed that [177Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively.

Conclusion

The uptake of [177Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11.

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Funding

This study was financially supported by NIH/NCI R01CA207645-0 (JO, NP), DoD PCRP Idea Award W81XWH-19-1-0536 (NP), and NIH/NCI R35 CA232130 (JSL) grants. Technical and facility services provided by the Center of Comparative Medicine & Pathology were supported in part by NIH Grant P30 CA008748. Dr. Chakraborty is supported by PCF young investigator award. 

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Authors and Affiliations

  1. Department of Radiology, Memorial Sloan Kettering Cancer Center, MSKCC Zuckerman Building, 417 E 68th St, New York, NY, 10065, USA

    Teja Muralidhar Kalidindi, Sang-Gyu Lee, Katerina Jou, Heiko Schoder, Lisa Bodei, Neeta Pandit-Taskar, Jason S. Lewis, Steven M. Larson & Naga Vara Kishore Pillarsetty

  2. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Goutam Chakraborty

  3. Department of Radiology, Weill Cornell Medicine, New York, NY, USA

    Myrto Skafida, Heiko Schoder, Lisa Bodei, Neeta Pandit-Taskar, Jason S. Lewis, Steven M. Larson, Joseph R. Osborne & Naga Vara Kishore Pillarsetty

  4. Department of Medicine, Weill Cornell Medicine, New York, NY, USA

    Scott T. Tagawa

  5. Department of Urology, Weill Cornell Medicine, New York, NY, USA

    Scott T. Tagawa & Neil H. Bander

  6. Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA

    Jason S. Lewis & Steven M. Larson

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  1. Teja Muralidhar Kalidindi
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  2. Sang-Gyu Lee
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Corresponding authors

Correspondence to Joseph R. Osborne or Naga Vara Kishore Pillarsetty.

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Conflict of interest

Dr. Tagawa has served as a consultant for Endocyte and Advanced Accelerator Applications/Novartis and has received institutional research funding from Advanced Accelerator Applications/Novartis. Cornell University holds the intellectual rights for anti-PSMA antibody technology invented by Dr. Bander, that has have been licensed to BZL Biologics, LLC. NB holds equity in BZL biologics and Telix Pharmaceuticals (also serves as uncompensated SAB). All other authors declare no conflict of interest.

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All animal studies were approved by MSKCC-IACUC that ensures that all international, national, and institutional guidelines for the care and use of animals were followed. This study does not contain any studies with human participants.

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Kalidindi, T.M., Lee, SG., Jou, K. et al. A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals. Eur J Nucl Med Mol Imaging 48, 2642–2651 (2021). https://doi.org/10.1007/s00259-020-05150-w

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