Microdistribution of Radium-223 Dichloride in Models of PC Bone Metastasis Studied

New Orleans—Radium-223 dichloride (Ra-223) is a first-in-class alpha particle emitter producing a survival benefit for patients with late stage bone metastatic castration-resistant prostate cancer (bmCRPC). Dosed at 45 kBq per kg every 4 weeks for six total injections, the bone seeking radionuclide delivers four high-energy alpha particles across a path length of only several cell diameters.

“Mechanism of action for the survival benefits is not fully understood, hampering our ability to best utilize this novel therapy,” according to Diane Abou, PhD, and colleagues. The researchers tested Ra-223 in naïve and bone metastatic models of disease, to define the whole body and suborgan distribution of the radionuclide. They results were reported during a session at the AUA 2015 Annual Meeting.

In this study, animals were dosed with 45 kBq of clinical grade Ra-223. Gamma counting in multiple skeletally mature murine models was used to monitor whole body distribution. Assessment of organ and whole body retention was done at 1, 4, and 24 hours. Cross-modality imaging of whole body and long bone autoradiography, histochemistry, and alpha-camera imaging of whole-mount, undecalcified tissues were used to assess detailed microdistribution of Ra-223. Uptake dependence and radiobiological effect of Ra-223 on bone morphology were evaluated by 10 mm isotropic resolution mCT (SkyScan).

“In contrast to previous preclinical work, our distribution studies recapitulate the planar scintigraphy results in man (EJNMMI, 2013), with Ra-223 accumulation observed in bowel stomach, and spleen,” the researchers said.

Whole-body autoradiography demonstrated the radioisotope bound to the contents of the digestive organs. Kinetic analysis revealed rapid clearance from the blood, as well as delayed clearance from both kidney and intestine.

In the bone, Ra-223 localized predominantly to the growth plates, largely sparing the marrow cavity. In models with bone metastasis, including the osteoblastic LNCaP, Ra-223 uptake was significantly lower than that in the epiphyseal.

The researchers said the study provided “greater understanding of the in vivo biological fate of this radiopharmaceutical with significant implications for enhances dosing strategies in bmCRPC.”

Source: Abou D, Ulmert D, Hobbs R, Riddle R, Thorek D. Microdistribution of Alpha Particle Emitting Radium-223 Dichloride in Models of Prostate Cancer Bone Metastasis. Abstract of presentation at the American Urological Association 2015 Annual Meeting, New Orleans, Louisiana, May 17, 2015.