Theranostic 64Cu-DOTHA2-PSMA allows low toxicity radioligand therapy in mice prostate cancer model

Marie-Christine Milot; Ophélie Bélissant-Benesty; Véronique Dumulon-Perreault; Samia Ait-Mohand; Sameh Geha; Patrick O Richard; Étienne Rousseau; Brigitte Guérin

doi:10.3389/fonc.2023.1073491

Theranostic ⁶⁴Cu-DOTHA₂-PSMA allows low toxicity radioligand therapy in mice prostate cancer model

Front Oncol. 2023 Jan 18:13:1073491. doi: 10.3389/fonc.2023.1073491. eCollection 2023.

Authors

Marie-Christine Milot¹, Ophélie Bélissant-Benesty¹, Véronique Dumulon-Perreault², Samia Ait-Mohand¹, Sameh Geha³, Patrick O Richard⁴, Étienne Rousseau^{1

2}, Brigitte Guérin^{1

2}

Affiliations

¹ Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
² Sherbrooke Molecular Imaging Center (CIMS), Centre de recherche du CHUS, Sherbrooke, QC, Canada.
³ Department of Pathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
⁴ Department of Surgery, Division of urology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.

Abstract

Introduction: We have previously shown that copper-64 (⁶⁴Cu)-DOTHA₂-PSMA can be used for positron emission tomography (PET) imaging of prostate cancer. Owing to the long-lasting, high tumoral uptake of ⁶⁴Cu-DOTHA₂-PSMA, the objective of the current study was to evaluate the therapeutic potential of ⁶⁴Cu-DOTHA₂-PSMA in vivo.

Methods: LNCaP tumor-bearing NOD-Rag1^nullIL2rg^null (NRG) mice were treated with an intraveinous single-dose of ⁶⁴Cu-DOTHA₂-PSMA at maximal tolerated injected activity, ^natCu-DOTHA₂-PSMA at equimolar amount (control) or lutetium-177 (¹⁷⁷Lu)-PSMA-617 at 120 MBq to assess their impact on survival. Weight, well-being and tumor size were followed until mice reached 62 days post-injection or ethical limits. Toxicity was assessed through weight, red blood cells (RBCs) counts, pathology and dosimetry calculations.

Results: Survival was longer with ⁶⁴Cu-DOTHA₂-PSMA than with ^natCu-DOTHA₂-PSMA (p < 0.001). Likewise, survival was also longer when compared to ¹⁷⁷Lu-PSMA-617, although it did not reach statistical significance (p = 0.09). RBCs counts remained within normal range for the ⁶⁴Cu-DOTHA₂-PSMA group. ⁶⁴Cu-DOTHA₂-PSMA treated mice showed non-pathological fibrosis and no other signs of radiation injury. Human extrapolation of dosimetry yielded an effective dose of 3.14 × 10^-2 mSv/MBq, with highest organs doses to gastrointestinal tract and liver.

Discussion: Collectively, our data showed that ⁶⁴Cu-DOTHA₂-PSMA-directed radioligand therapy was effective for the treatment of LNCaP tumor-bearing NRG mice with acceptable toxicity and dosimetry. The main potential challenge is the hepatic and gastrointestinal irradiation.

Keywords: DOTHA2-PSMA; copper-64; prostate cancer; radioligand therapy; theranostic.

Grants and funding

This research received financial support from the Oncopole (funded by Merck Canada Inc., Fonds de recherche du Québec – Santé (FRQS), and the Cancer Research Society). MC Milot received scholarships from the Canadian Institute of Health Research, FRQS, and the University of Sherbrooke (UdS). B Guérin is the holder of the Jeanne and J.-Louis Lévesque Chair in Radiobiology at the Université de Sherbrooke. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication. All authors declare no other competing interests.