PNNL

Abstract

The bone-seeking property of and the potential to irradiatiate red marrow by the alpha-particle emitter Ra-223 (t1/2 = 11.43 d) were compared to those of the beta-emitter Sr-89 (t1/2 = 50.53 d). Methods: The biodistributions of Ra-223 and Sr-89 were studied in mice. Tissue uptakes were determined at 1 h, 6 h, 1 d, 3 d, and 14 d after intravenous administration. The potential redistribution of progeny from Ra-223 located in bone was investigated. Radiation absorbed doses were calculated for soft tissues and bone. Doses were also estimated for marrow-containing cavities assuming spheric geometries. Results: We found that both Sr-89 and Ra-223 selectively concentrated on bone surfaces relative to soft tissues. The measured bone uptake of Ra-223 was slightly higher than that of Sr-89. At the 24 h time-point, the femur uptake of Ra-223 was 40.1% of the administered activity per gram tissue. The uptake in spleen and most other soft tissues was higher for Ra-223 than for Sr-89. We observed rapid clearance of Ra-223 from soft tissues within the first 24 hours, but the bone surface uptake of Ra-223 increased with time up to 24 h. Among the soft tissues, the spleen had the greatest accumulation and retention of Ra-223. The femur-to-spleen ratio increased with time, from 6.4 at 6 h to 23.7 at 3 days after injections. We found little redistribution of Ra-223 daughter products away from bone (about 2% at 6 h and less than 1% detectable at 3 d). Estimates of dose to marrow-containing cavities showed that the Ra-223 alpha-emitter might have a marrow-sparing advantage compared to beta-emitters due to high high linear-energy-transfer and short alpha range targeting osteoid surfaces. The alpha-emitters irradiate a smaller fraction of the marrow-containing volumes--sparing marrow and enhancing survival of marrow cells. At the same time, the bone surfaces receives a therapeutically effective radiation dose. Conclusion: The results of this study indicate that Ra-223 is a promising candidate for high linear-energy-transfer alpha-particle irradiation of cancer cells on bone surfaces. Radium-223 can, together with its daughter radionuclides, deliver an intense and highly localized field of radiation to bone surfaces with substantially less irradiation of healthy bone marrow dose compared to standard, bone-seeking beta-emitters such as Sr-89.