Stochastic simulation of radium-223 dichloride therapy at the sub-cellular level

Abstract

Radium-223 dichloride ((223)Ra) is an alpha particle emitter and a natural bone-seeking radionuclide that is currently used for treating osteoblastic bone metastases associated with prostate cancer. The stochastic nature of alpha emission, hits and energy deposition poses some challenges for estimating radiation damage. In this paper we investigate the distribution of hits to cells by multiple alpha particles corresponding to a typical clinically delivered dose using a Monte Carlo model to simulate the stochastic effects. The number of hits and dose deposition were recorded in the cytoplasm and nucleus of each cell. Alpha particle tracks were also visualized. We found that the stochastic variation in dose deposited in cell nuclei ([Formula: see text]40%) can be attributed in part to the variation in LET with pathlength. We also found that [Formula: see text]18% of cell nuclei receive less than one sigma below the average dose per cell ([Formula: see text]15.4 Gy). One possible implication of this is that the efficacy of cell kill in alpha particle therapy need not rely solely on ionization clustering on DNA but possibly also on indirect DNA damage through the production of free radicals and ensuing intracellular signaling.

Radio-enhancement effects by radiolabeled nanoparticles

“…Additionally, although the number of Auger electrons decreases at SD >50 nm for all radio-FH sources, the number generated by 213 Bi-FH and 223 Ra-FH remains above that of the number generated by other radio-FH sources. This is mainly due to the higher linear energy transfer (LET) of alpha particles (compared to β − particles) and the stochastic nature of their energy deposition 21 . The number of Auger electrons produced in water only (i.e.…”

“…external beam radiotherapy). Targeted internal radionuclide therapy is an alternative treatment approach to achieve more localized radiotherapy by delivering a radioisotope internally to a tumor 21,22 . Nanoparticles can be labeled with various radioisotopes for use in both internal radionuclide therapy and diagnostic imaging (emission tomography) 23 .…”

Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators

“…The studies published so far did not evaluate the complete decay and the energy distribution in decay products even though microautoradiographic techniques, in a combination with immuno-staining methods, are available [ 71 ]. Single α particle-induced damage visualized in real time was also reported [ 72 ] and the stochastic simulation of 223 Ra α particle irradiation effects on subcellular level was recently performed [ 73 ]; however, recoils were not taken into account. The cell-to-cell fluctuations in dose deposition ranged up to about 40%.…”

Targeted Alpha Therapy: Current Clinical Applications

“…It is clear from the physical characteristics of TAT that due the short path length of a particles relative to target dimensions and incomplete targeting, some cell nuclei receive multiple hits, while others receive no direct irradiation, giving rise to an inhomogeneous irradiation profile. 30 Those cells that are not directly irradiated may diminish the overall therapeutic benefit. Because of this, early studies had predicted some advantage of b --emitting radionuclides in macrolesions due to the cross-fire effect (dose delivered outside the targeted cell due to long particle ranges), reducing problems associated with heterogeneous uptake in the target.…”