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

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.

LNCaP tumor-bearing NOD-Rag1 (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.

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.

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.