Monte Carlo study of gold nanoparticle-mediated radiosensitization effects using nanoscale cell model combined with fractal-based DNA model.

Abstract

Background: Gold nanoparticles (GNPs) are promising radiosensitizers in radiation therapy, yet the exact mechanisms behind their effectiveness remain not fully understood. Monte Carlo (MC) simulations have been used to study extra energy deposition and increased DNA damage by the secondary electrons from intracellularly present GNPs, which are believed to be the key physical mechanisms responsible for the radiosensitization effects observed in many radiobiological studies. However, discrepancies between experimental results and computational predictions persist. While often attributed to purely biological effects, such discrepancies, from a physical modeling point of view, can also be due to the use of MC models constructed with simplified cellular/DNA geometries and unrealistic GNP distributions. To address this challenge, higher-resolution nanoscale models with realistic GNP distributions and detailed cellular/DNA structures are needed. In principle, computational results from such nanoscale models can be not only more accurate but also directly correlated with experimental results for biological outcome modeling.

Purpose: The main purpose of this MC study was to investigate the potential increase in radiation-induced DNA damage due to internalized GNPs by using a nanoscale cell model including realistic GNP distributions and detailed cellular/DNA structures.

Methods: Two high-resolution nanoscale cellular geometry models, featuring the nucleus filled with fractal-patterned DNA fibers, were constructed from transmission electron microscopy (TEM) images of GNP-laden human colorectal tumor cells. These models were used to simulate the initial yield of single- and double-strand breaks (SSBs and DSBs) of DNA under orthovoltage (250 kVp) and megavoltage (6 MV) photon beam irradiation. In-depth Geant4 MC simulations were conducted to assess radiation-induced effects due to intracellular GNP presence and absence, focusing on the computation of SSBs/DSBs and their causative mechanisms - direct or indirect effects of ionizing radiation. Penelope and Geant4-DNA for Gold (G4_DNA_Au) physics models were employed for GNPs, and the difference between those two physics models were also evaluated.

Results: The simulation results revealed a notable enhancement in the nucleus dose and DNA damage due to intracellular GNP presence, with maximum dose enhancements observed at 4.24% and 4.34% for 250 kVp, and 3.04% and 3.22% for 6 MV irradiation using the Penelope and G4_DNA_Au physics models, respectively. Crucially, this study found that indirect yields of both SSB and DSB were significantly higher than their direct counterparts, emphasizing the dominance of indirect DNA damage mechanisms. SSB enhancements were recorded between 2.36% and 3.46%, while DSB enhancements were more significant, ranging from 7.36% to 10.33%, across various scenarios and photon energies under the G4_DNA_Au physics model. The 250 kVp beam showed more SSB enhancement, whereas the 6 MV beam yielded more DSB enhancement.

Conclusion: With a realistic fractal-based chromatin fiber arrangement of DNA within the nucleus, the currently developed TEM-based cellular geometry model enabled the unprecedented investigation of radiation-induced DNA damage in a single GNP-laden cell using track structure Geant4 MC simulations. The modeling approaches and findings from this study significantly enhance our ability and knowledge to conduct computational investigations of GNP-mediated radiosensitization, possibly leading to the development of a predictive biological outcome model with minimal empiricism.