Purpose: We describe a nephron‐based dosimetry model for renal toxicity for alpha‐particle radipharmaceutical therapy suited to the short range and high linear energy transfer of alpha‐particle emitters. This model is applied to Ac‐225‐7.16.4 radioimmunotherapy of murine metastatic breast cancer, where renal toxicity is observed for whole‐kidney and renal cortex absorbed dose values below toxicity thresholds established by external beam and targeted radiopeptide therapy. Methods: Using GEANT4 Monte Carlo software an idealized nephron model is created using geometrical and anatomical parameters taken from the literature and from murine samples. These samples also provide the data for volume of occupancy of the different compartments of the nephron in the kidney: glomerulus vs. proximal tubule vs. distal tubule. Radiopharmaceutical uptake in the different components of potential toxicity from (a) bound Ac‐225 and (b) free Bi‐213 are taken from experimental data and the literature and supplemented by tissue imaging with a beta‐Imager. Monte Carlo simulations were run, the absorbed doses to the model components were calculated and the results compared to experimental observations of renal toxicity. The renal cortex and medulla absorbed doses were also calculated and the results compared to traditional absorbed fraction results. Results: Preliminary results show an absorbed dose to the proximal tubule and glomerular cells approximately 3 times greater than that to the nephron as a whole. This difference in conjunction with the relative biological effect of alpha particles (a factor of about 5) would be consistent with the toxicity observed in the murine experiments. The renal cortex and renal medulla absorbed doses are consistent with the absorbed fraction methodology. Conclusions: Alpha‐particle radipharmaceutical therapy is a promising treatment modality for cancer. The nephron model enables optimal implementation of treatment and is a critical step in understanding toxicity for human translation of alpha‐particle radiopharmaceutical therapy.
ASJC Scopus subject areas
- Radiology Nuclear Medicine and imaging