Purpose: The mechanism of action of ²²³Ra-dichloride is not well understood despite the growing use of the radiopharmaceutical for the treatment of metastatic castrate-resistant prostate cancer in the bone. To support preclinical studies of ²²³Ra-dichloride we have developed an advanced microdosimetric model that combines a detailed anatomical model of bony anatomy and a whole-body pharmacokinetic (PK) model of radium once injected into the blood.
Methods: A high-resolution CT scan (10 μm x 10 μm x 10 μm) was taken of a mouse femur ex vivo using the MiLabs U-CT scanner(MiLabs, Netherlands). Multiple geometric regions in a section of the bone were segmented in MATLAB (MathWorks Inc., Natick, MA) using an intensity-based analysis. The non-uniform activity distribution of ²²³Ra-dichloride was calculated in the bony anatomy based on the whole-body PK model of radium provided in the ICRP Report 137 using advanced PK modeling with the SimBiology application in MATLAB. Microdosimetric simulations were performed in the model using the general-purpose Monte Carlo code Geant4 accounting for the decay products of ²²³Ra and its daughters.
Results: The results of the PK modeling of the bony anatomy indicate that the endosteum and the cortical surface components showed the most rapid uptake and clearance. The non-exchangeable cortical and trabecular volumes showed the slowest uptake and clearance. The mean dose to the trabecular, endosteum, and marrow components were in accordance with previously published values.
Conclusion: This work offers a method to understand the dosimetric behavior of ²²³Ra-dichloride via the combined use of PK modeling, a microCT based geometric model, and GEANT4 Monte Carlo simulations. The model may provide further insight into the behavior of ²²³Ra-dichloride and lead to more effective determinations of normal tissue toxicity and therapeutic efficacy of metastatic castrate-resistant prostate cancer treatment regimens.
Funding Support, Disclosures, and Conflict of Interest: BB is a co-founder of Voximetry, Inc., a nuclear medicine dosimetry company in Madison, WI. JJ is a co-founder of Phantech Medical, a nuclear medicine phantom company in Madison, WI.