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

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

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1073491

DOI=10.3389/fonc.2023.1073491

ISSN=2234-943X

ABSTRACT=<sec><title>Introduction</title><p>We have previously shown that copper-64 (<sup>64</sup>Cu)-DOTHA<sub>2</sub>-PSMA can be used for positron emission tomography (PET) imaging of prostate cancer. Owing to the long-lasting, high tumoral uptake of <sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA, the objective of the current study was to evaluate the therapeutic potential of <sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA <italic>in vivo</italic>.</p></sec><sec><title>Methods</title><p>LNCaP tumor-bearing NOD-<italic>Rag1<sup>null</sup>IL2rg<sup>null</sup></italic> (NRG) mice were treated with an intraveinous single-dose of <sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA at maximal tolerated injected activity, <sup>nat</sup>Cu-DOTHA<sub>2</sub>-PSMA at equimolar amount (control) or lutetium-177 (<sup>177</sup>Lu)-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.</p></sec><sec><title>Results</title><p>Survival was longer with <sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA than with <sup>nat</sup>Cu-DOTHA<sub>2</sub>-PSMA (<italic>p</italic> &lt; 0.001). Likewise, survival was also longer when compared to <sup>177</sup>Lu-PSMA-617, although it did not reach statistical significance (<italic>p</italic> = 0.09). RBCs counts remained within normal range for the <sup>64</sup>Cu-DOTHA<sub>2</sub>-PSMA group. <sup>64</sup>Cu-DOTHA<sub>2</sub>-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<sup>-2</sup> mSv/MBq, with highest organs doses to gastrointestinal tract and liver.</p></sec><sec><title>Discussion</title><p>Collectively, our data showed that <sup>64</sup>Cu-DOTHA<sub>2</sub>-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.</p></sec>