Modelling direct DNA damage for gold nanoparticle enhanced proton therapy

Gold nanoparticles have been proven as potential radiosensitizer when combined with protons. Initially the radiosensitization effect was attributed to the physical interactions of radiation with the gold and the production of secondary electrons that induce DNA damage. However, emerging data challenge this hypothesis, supporting the existence of alternative or supplementary radiosensitization mechanisms. In this work we incorporate a realistic cell model with detailed DNA geometry and a realistic gold nanoparticle biodistribution based on experimental data. The DNA single and double strand breaks, and damage complexity are counted under various scenarios of different gold nanoparticle size, biodistribution and concentration, and proton energy. The locality of the effect, i.e. the existence of higher damage at a location close to the gold distribution, is also addressed by investigating the DNA damage at a chromosomal territory. In all the cases we do not observe any significant increase in the single/double strand break yield or damage complexity in the presence of gold nanoparticles under proton irradiation; nor there is a locality to the effect. Our results show for the first time that the physical interactions of protons with the gold nanoparticles should not be considered directly responsible for the observed radiosensitization effect. The model used only accounts for DNA damage from direct interactions, whilst considering the indirect effect, and it is possible the radiosensitization effect to be due to other physical effects, although we consider that possibility unlikely. Our conclusion suggests that other mechanisms might have greater contribution to the radiosensitization effect and further investigation should be conducted.