Theranostic Cu-DOTHA-PSMA allows low toxicity radioligand therapy in mice prostate cancer model.

INTRODUCTION

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

METHODS

LNCaP tumor-bearing NOD- (NRG) mice were treated with an intraveinous single-dose of Cu-DOTHA-PSMA at maximal tolerated injected activity, Cu-DOTHA-PSMA at equimolar amount (control) or lutetium-177 (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.

RESULTS

Survival was longer with Cu-DOTHA-PSMA than with Cu-DOTHA-PSMA ( < 0.001). Likewise, survival was also longer when compared to Lu-PSMA-617, although it did not reach statistical significance ( = 0.09). RBCs counts remained within normal range for the Cu-DOTHA-PSMA group. Cu-DOTHA-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 mSv/MBq, with highest organs doses to gastrointestinal tract and liver.

DISCUSSION

Collectively, our data showed that Cu-DOTHA-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.