Development and In Vitro Evaluation of [64Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer

Talebian, Hoda; Ait-Mohand, Samia; Ignatius Arokia Doss, Prenitha Mercy; Sanche, Léon; Guérin, Brigitte

doi:10.3390/ijms262311651

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Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer

by

Hoda Talebian

¹,

Samia Ait-Mohand

¹,

Prenitha Mercy Ignatius Arokia Doss

¹,

Léon Sanche

^1,2

and

Brigitte Guérin

^1,2,3,*

¹

Department of Medical Imaging and Radiation Sciences, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada

²

Institut de Recherche sur le Cancer de l’Université de Sherbrooke (IRCUS), Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada

³

Sherbrooke Molecular Imaging Center (CIMS), Centre de Recherche du CHUS (CRCHUS), Sherbrooke, QC J1H 5H3, Canada

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2025, 26(23), 11651; https://doi.org/10.3390/ijms262311651 (registering DOI)

Submission received: 28 October 2025 / Revised: 28 November 2025 / Accepted: 29 November 2025 / Published: 1 December 2025

(This article belongs to the Special Issue Emerging Topics in Metal Complexes: Pharmacological Activity, 2nd Edition)

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Abstract

Prostate cancer (PCa), particularly in its metastatic form, remains a major clinical challenge due to limited diagnostic and therapeutic options. To address this, we developed a novel radiotheranostic agent, [⁶⁴Cu]Cu-NOTA-TP-PSMA, by conjugating a prostate-specific membrane antigen (PSMA) ligand to a ⁶⁴Cu-radiolabeled terpyridine-platinum (TP) compound previously shown to exert selective cytotoxicity against cancer cells. In this study, the biological performance of [⁶⁴Cu]Cu-NOTA-TP-PSMA was compared with the monomeric analogs [⁶⁴Cu]Cu-NOTA-PSMA and [⁶⁴Cu]Cu-NOTA-TP through in vitro studies in PSMA-positive LNCaP prostate cancer cells and non-malignant HEK-293 cells. [⁶⁴Cu]Cu-NOTA-TP-PSMA showed high stability, PSMA binding affinity and exhibited substantially enhanced uptake, internalization, retention, and nuclear localization in LNCaP cells relative to the monomers, whereas uptake and nuclear accumulation in HEK-293 cells were negligible. Cytotoxicity assays further demonstrated potent and selective activity in LNCaP cells, with EC₅₀ values in the low nanomolar range, and minimal toxicity in HEK-293 cells. Collectively, these results identify [⁶⁴Cu]Cu-NOTA-TP-PSMA as a promising radiotheranostic agent, warranting further in vivo evaluation for prostate cancer imaging and targeted radiotherapy.

Keywords: prostate cancer; PSMA; radiotheranostic agent; copper-64; terpyridine-platinum; in vitro validation

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MDPI and ACS Style

Talebian, H.; Ait-Mohand, S.; Ignatius Arokia Doss, P.M.; Sanche, L.; Guérin, B. Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer. Int. J. Mol. Sci. 2025, 26, 11651. https://doi.org/10.3390/ijms262311651

AMA Style

Talebian H, Ait-Mohand S, Ignatius Arokia Doss PM, Sanche L, Guérin B. Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer. International Journal of Molecular Sciences. 2025; 26(23):11651. https://doi.org/10.3390/ijms262311651

Chicago/Turabian Style

Talebian, Hoda, Samia Ait-Mohand, Prenitha Mercy Ignatius Arokia Doss, Léon Sanche, and Brigitte Guérin. 2025. "Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer" International Journal of Molecular Sciences 26, no. 23: 11651. https://doi.org/10.3390/ijms262311651

APA Style

Talebian, H., Ait-Mohand, S., Ignatius Arokia Doss, P. M., Sanche, L., & Guérin, B. (2025). Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer. International Journal of Molecular Sciences, 26(23), 11651. https://doi.org/10.3390/ijms262311651

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Development and In Vitro Evaluation of [⁶⁴Cu]Cu-NOTA-TP-PSMA, a Novel Radiotheranostic Agent Against Prostate Cancer

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