Modeling Cell and Tumor-Metastasis Dosimetry with the Particle and Heavy Ion Transport Code System (PHITS) Software for Targeted Alpha-Particle Radionuclide Therapy

Abstract

The use of targeted radionuclide therapy for cancer is on the rise. While beta-particle-emitting radionuclides have been extensively explored for targeted radionuclide therapy, alpha-particle-emitting radionuclides are emerging as effective alternatives. In this context, fundamental understanding of the interactions and dosimetry of these emitted particles with cells in the tumor microenvironment is critical to ascertaining the potential of alpha-particle-emitting radionuclides. One important parameter that can be used to assess these metrics is the S-value. In this study, we characterized several alpha-particle-emitting radionuclides (and their associated radionuclide progeny) regarding S-values in the cellular and tumor-metastasis environments. The Particle and Heavy Ion Transport code System (PHITS) was used to obtain S-values via Monte Carlo simulation for cell and tumor metastasis resulting from interactions with the alpha-particle-emitting radionuclides, lead-212 (²¹²Pb), actinium-225 (²²⁵Ac) and bismuth-213 (²¹³Bi); these values were compared to the beta-particle-emitting radionuclides yttrium-90 (⁹⁰Y) and lutetium-177 (¹⁷⁷Lu) and an Auger-electron-emitting radionuclide indium-111 (¹¹¹In). The effect of cellular internalization on S-value was explored at increasing degree of internalization for each radionuclide. This aspect of S-value determination was further explored in a cell line-specific fashion for six different cancer cell lines based on the cell dimensions obtained by confocal microscopy. S-values from PHITS were in good agreement with MIRDcell S-values (cellular S-values) and the values found by Hindié et al. (tumor S-values). In the cellular model, ²¹²Pb and ²¹³Bi decay series produced S-values that were 50- to 120-fold higher than ¹⁷⁷Lu, while ²²⁵Ac decay series analysis suggested S-values that were 240- to 520-fold higher than ¹⁷⁷Lu. S-values arising with 100% cellular internalization were two- to sixfold higher for the nucleus when compared to 0% internalization. The tumor dosimetry model defines the relative merit of radionuclides and suggests alpha particles may be effective for large tumors as well as small tumor metastases. These results from PHITS modeling substantiate emerging evidence that alpha-particle-emitting radionuclides may be an effective alternative to beta-particle-emitting radionuclides for targeted radionuclide therapy due to preferred dose-deposition profiles in the cellular and tumor metastasis context. These results further suggest that internalization of alpha-particle-emitting radionuclides via radiolabeled ligands may increase the relative biological effectiveness of radiotherapeutics.

FIG. 1.

Decay schemes of the radionuclides investigated. Two beta-particle-emitting radionuclides ⁹⁰Y and ¹⁷⁷Lu, one Auger-electron-emitting radionuclide ¹¹¹In and three alpha-particle-emitting radionuclides ²¹²Pb, ²²⁵Ac, and ²¹³Bi were included for this study. Note ²¹³Bi is one of the downstream radionuclides of ²²⁵Ac decay.

FIG. 2.

Depth-dose distributions of the alpha particles emitted per decay of (panels A–C, respectively) ²¹²Pb, ²²⁵Ac and ²¹³Bi decay series in water slabs. The initial and maximum LETs and corresponding ranges of the alpha particles were determined based on the distributions. The branching ratios were considered.

FIG. 3.

Percentage difference between cellular S-values obtained from PHITS simulation and MIRDcell software version 2.0.16 (43) for the radionuclides investigated.

FIG. 4.

Dose deposition as a function of cellular internalization. Panel A: Cross-sectional dose deposition resulted from ¹⁷⁷Lu with increasing degree of internalization (by 20% increment). The effect of internalization of the radionuclides investigated on S-values for the nucleus (panel B) and whole cell model (panel C). The ratios between the S-values from 100% vs. 0% internalization are represented as increase factor (IF) on the right sides of the graphs.

FIG. 5.

Confocal microscopy images of six human cancer cell lines. Averaged volumes of the cells and the nuclei were estimated from confocal z-stacks (at least 30-cell images) and translated to the radii of the cell (R_C) and the nucleus (R_N) assuming the cell and the nucleus were in sphere shapes. R_N/R_C represents the ratio between the cell and the nucleus radii and is regarded as a parameter for susceptibility from internalization.

FIG. 6.

Percentage difference between the tumor S-values obtained from PHITS simulation and from Hindié et al. (33) for ¹⁷⁷Lu, ⁹⁰Y and ¹¹¹In. Simulations were repeated for ¹¹¹In with and without photon specification in the source section.

FIG. 7.

Dose deposition to 10-μm-diameter cell vs. 1-cm-diameter tumor metastasis and contribution of each type of radiation to final dose from the decays of radionuclides investigated. Panel A: Cross-sectional dose depositions in 10-μm cells (upper panels) and 1-cm tumor metastases (lower panels) resulted from the decays of beta-particle-emitting radionuclides ⁹⁰Y and ¹⁷⁷Lu, and ²¹²Pb decay series as a representative of the alpha-decay series. Panel B: Radiation dose deposited and each type of radiation emitted from the radionuclides under investigation in 10-μm cells (left panel) and 1-cm tumor metastases (right panel).