Therapeutic Effect of α-Emitting 224Ra-Labeled Calcium Carbonate Microparticles in Mice with Intraperitoneal Ovarian Cancer

Abstract

BACKGROUND: Ovarian cancer patients with chemotherapy-resistant residual microscopic disease in the peritoneal cavity have a considerable need for new treatment options. Alpha-emitting radionuclides injected intraperitoneally may be an attractive therapeutic option in this situation as they are highly cytotoxic, while their short range in tissues can spare surrounding radiosensitive organs in the abdomen. Herein we evaluate the therapeutic efficacy of a novel α-emitting compound specifically designed for intracavitary radiation therapy. METHODS: The α-emitter 224Ra was absorbed on calcium carbonate microparticles. Immunodeficient, athymic nude mice with human ovarian cancer cells growing intraperitoneally were treated with different activity levels of 224Ra-microparticles. Tumor growth, survival, and tolerance of the treatment were assessed. Two tumor models based on the cell lines, ES-2 and SKOV3-luc, with different growth patterns were studied. RESULTS: In both models, intraperitoneal treatment with 224Ra-microparticles gave significant antitumor effect with either considerably reduced tumor volume or a survival benefit. An advantageous discovery was that only a few kilobecquerels per mouse were needed to yield therapeutic effects. The treatment was well tolerated up to a dose of 1000 kBq/kg with no signs of acute or subacute toxicity observed. CONCLUSIONS: Intraperitoneal α-therapy with 224Ra-microparticles demonstrated a significant potential for treatment of peritoneal micrometastases in ovarian carcinoma.

Ra‐224 labeling of calcium carbonate microparticles for internal α‐therapy: Preparation, stability, and biodistribution in mice

“…Exploring alternative formulations for injection to obtain a less heterogenous microparticle distribution in the peritoneal cavity is also of interest. In mice studies, 150 to 1000 kBq/kg of 224 Ra‐labeled CaCO 3 microparticles seems to be therapeutically relevant and well‐tolerated . If this, together with the microparticle doses of 5 to 25 mg used in this study, is to be translated into human equivalent doses according to the procedure recommended by the FDA, doses of 0.5 to 3 MBq/m 2 and 0.6 to 3 g/m 2 are obtained.…”

Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

“…High labelling yields as well acceptable in vitro and in vivo stabilities over the period of 223 Ra half-life make the developed nanoconstructs promising for targeted cancer therapy, e.g., bone matrix targeting [ 17 ]. Similarly, the 223 Ra labelled CaCO 3 microparticles were successfully tested in a mice model with ES-2 and SKOV3-luc intraperitoneal ovarian cancer xenografts resulting in considerably reduced tumor volume or a survival benefit [ 105 ].…”

Current Aspects of Radiopharmaceutical Chemistry

“…Siebold and coworkers described the rational design and solid phase synthesis of CTH36 (16) as a ligand for 89 Zr chelation ( Figure 5) [105]. To maximize the potential of this new ligand its rational design was predicated on extensive computational studies and several important design characteristics including (1) the inclusion of four hydroxamate coordinating units; (2) a macrocyclic structure to take advantage of the macrocyclic effect; (3) rotational symmetry to limit isomers; (4) hydrophilic character; and (5) an optimal cavity size to provide a balance between ring strain and entropic effects.…”

“…Similarly, the 223 Ra labelled CaCO 3 microparticles were successfully tested in a mice model with ES-2 and SKOV3-luc intraperitoneal ovarian cancer xenografts resulting in considerably reduced tumor volume or a survival benefit [105].…”

“…Seo et al conducted PET imaging-guided systematic development of BBB-permeable HDAC inhibitors (Table 4) [105]. They repeated radiosynthesis, performed PET imaging in the baboon brain, and incorporated the imaging data into the compound design.…”