Abstract 3922: Biodistribution of Ra-224 and its daughter Pb-212 after intraperitoneal infusion of Ra-224 labeled microparticles in rats

Abstract

Introduction: Radium-224 (Ra-224) labeled calcium carbonate (CaCO3) microparticles were developed with the intent to treat micrometastases located in the abdominal cavity. The slowly degradable microparticles act as carriers for the α-emitter Ra-224 and ensure high intraperitoneal (IP) retention of the radioactivity without cellular targeting. This novel α-therapy has a short action range in tissue and is designed to confine the radiation exposure to the IP cavity, treating both linings of the peritoneal surfaces and liquid volumes. The distribution of the Ra-224 labeled microparticles was examined by planar gamma imaging, SPECT and CT. The ex vivo biodistribution of Ra-224 and its progeny Pb-212 was also determined. Experimental procedures: Fifteen female Wistar rats were infused IP with Ra-224-labeled microparticles (200-400 kBq, 100 mg CaCO3). The injections were performed by use of a perforated catheter (pigtail catheter), followed by a Plasmalyte flush to mimic the planned clinical administration. The Ra-224 labeled microparticles were imaged using both planar gamma imaging, SPECT and CT to evaluate the distribution over time in the abdominal region. Ex vivo biodistribution was performed 2, 24, 96, 168 and 336 hours after particle infusion and organs were harvested for activity measurements. The activity was determined at 2 hours and 48 hours after harvesting for all samples. This allowed differentiation between the biodistribution of Ra-224 and the biodistribution of its progeny Pb-212. Furthermore, 4 rats were injected IP with free Ra-224 and 2 rats were injected intravenously with free Ra-224 to achieve a baseline for the biodistribution. These control animals were euthanized at 24 and 168 hours, and 168 hours, respectively. Results: Based on both CT and SPECT images, the particles distributed to the entire peritoneum, albeit with local areas of high microparticle concentration. Over the course of the experiment there was, as expected, a modest but evident systemic leakage of Ra-224 from the particles in the peritoneal cavity. The amount was estimated by the bone uptake of radioisotopes Pb-212 and Ra-224, using IP administered free Ra-224 as reference. The retention of Ra-224 in the peritoneal cavity was found to be > 87% at 24 hours and > 77% at 168 hours. Redistribution of the progeny Pb-212 was observed as modest uptake in the kidneys. Conclusions: High peritoneal retention of both Ra-224 and its progeny Pb-212 after IP injection of Ra-224 labeled CaCO3 microparticles, was found in rats with high translational value to the clinical setting. SPECT imaging supported distribution of the Ra-224 labeled microparticles to the entire peritoneal lumen in the animals. SPECT and CT revealed some clusters of labeled microparticles. Due to the short range of the therapeutic relevant α-particles, the clusters are not expected to have an impact on therapeutic or safety aspects. Citation Format: Jesper Fonslet, Carsten H. Nielsen, Lotte K. Kristensen, Ida S. Jorstad, Kim Lindland, Roy H. Larsen, Øyvind S. Bruland, Andreas Kjaer, Tina B. Bønsdorff. Biodistribution of Ra-224 and its daughter Pb-212 after intraperitoneal infusion of Ra-224 labeled microparticles in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3922.