Intraperitoneal alpha therapy with (224)Ra-labeled microparticles combined with chemotherapy in an ovarian cancer mouse model

A novel alpha-therapy consisting of (224)Ra-labeled calcium carbonate microparticles ((224)Ra-CaCO(3)-MP) has been designed to treat micrometastatic peritoneal disease via intraperitoneal (IP) administration. This preclinical study aimed to evaluate its efficacy and tolerability when given as a single treatment or in combination with standard of care chemotherapy regimens, in a syngeneic model of ovarian cancer in immune competent mice. Female C57BL/6 mice bearing ID8-fLuc ovarian cancer were treated with (224)Ra-CaCO(3)-MP 1 day after IP tumor cell inoculation. The activity dosages of (224)Ra ranged from 14 to 39 kBq/mouse. Additionally, (224)Ra-CaCO(3)-MP treatment was followed by either carboplatin (80 mg/kg)-pegylated liposomal doxorubicin (PLD, 1.6 mg/kg) or carboplatin (60 mg/kg)-paclitaxel (10 mg/kg) on day 14 post tumor cell inoculation. All treatments were administered via IP injections. Readouts included survival, clinical signs, and body weight development over time. There was a slight therapeutic benefit after single treatment with (224)Ra-CaCO(3)-MP compared to the vehicle control, with median survival ratios (MSRs) ranging between 1.1 and 1.3. The sequential administration of (224)Ra-CaCO(3)-MP with either carboplatin-paclitaxel or carboplatin-PLD indicated a synergistic effect on overall survival at certain (224)Ra activities. Moreover, the combinations tested appeared well tolerated in terms of weight assessment in the first 4 weeks after treatment. Overall, this research supports the further evaluation of (224)Ra-CaCO(3)-MP in patients with ovarian cancer. However, the most optimal chemotherapy regimen to combine with (224)Ra-CaCO(3)-MP should be identified to fully exploit its therapeutic potential.