The paper of Polf et al.1 reports a decrease of cell prostate tumour survival rate when the cells are loaded with gold nanoparticles and irradiated by 160 MeV protons with a spread out Bragg peak (SOBP) of 10 cm. They interpret this finding as due to a dose enhancement resulting from an increase in low energy x-rays emission from the tumour and an increase of the dose within the tumour cells. In addition, they explain the change in the shape of the survival curve in presence of gold atoms as a result of the proton-Au interaction which results in an increase in the ionisation density-Z atoms.
We do not believe that the different mechanisms proposed by these authors have a significant role in the cell death induction. Different experiments have been made by our group years ago, at the Photon Factory and at the Heavy Ion Medical Accelerator (HIMAC) located, respectively, in Tsukuba and in Chiba (Japan), to study the biological effects of the combination of irradiation by ionising particles—monochromatic photons and atomic ions—and the addition of heavy atoms like platinum, gadolinium, or gold contained in molecules or nanoparticles in order to improve the therapeutic index of the protontherapy or, more generally, the hadrontherapy.2–9 We believe that Polf et al. should interpret their results in the light of our previous works concerning the enhancement of DNA damages or cell death rate in presence of added high-Z atoms irradiated by atomic ions.
The increase in DNA damages or cell death rate in presence of high-Z atoms must be compared for the same physical dose between the results obtained with and without heavy atoms. The concept of “dose enhancement or reinforcement of dose,” commonly used, is a little bit misleading. The terminology “enhancement of the effect of the dose” should be used instead. The latter concept is related to the familiar relative biology efficiency.
The authors Polf et al. do not present any results of experiments performed in the presence of free radicals scavengers. In our experiments—made with or without heavy atoms—we have observed that in presence of free radical scavenger, like dimethyl sulfoxide (DMSO), the effects of irradiation are decreased by about 80%. Hence, it can be concluded that the major part of the mechanisms is free radicals mediated even in presence of additional high-Z atoms.
To explain these findings, we have suggested the following mechanisms to interpret the enhancement of the biological damages or cell death rate by ionising particles in presence of high-Z atoms. These mechanisms are proposed following the analysis of the results of the experiments and discussion in Refs. 2–9 involving the study of resonant photoabsorption of x-rays and different experiments with atomic ions—helium He2+, carbon C6+, iron Fe26+—with a linear energy transfer (LET) ranging from 2 keV/μm up to 500 keV/μm.
The energetic secondary electrons generated on the primary tracks of the incident ions are able to induce the innershell ionisation of the heavy atoms. The relaxation of the excited core takes place mainly by Auger effect. The contribution of the radiative channel (fluorescence) is much less important. The direct excitation by impact of the incident atomic ion on the heavy-atom is possible, but the probability of such mechanism was found to be low.2–9 The Auger electrons emitted by the heavy atoms induce the radiolysis of the surrounding water molecules as shown by the experiments performed in presence of free radical scavengers. The clusters of free radicals, in particular, the free hydroxyl radicals HO•, induces molecular damages by free radicals attacks or cell death due to a large oxidative stress. One of our results presented in Ref. 5 shows that the heavy atoms need not to sit in the cell nucleus to trigger a significant cell death enhancement.
Briefly speaking, there is no enhancement of the energy deposition but a conversion of the energy of the secondary electrons in Auger de-excitation in the heavy atoms. As a result, the Auger effects induce a large oxidative stress due to the water radiolysis which induces the cell death enhancement.
It cannot be excluded, in particular, in experiments involving gold, in which a pharmacologic effect exists. Gold atoms can be at different oxidation states following irradiation and might migrate through the cytoplasm and react on the thiols (glutathion, GSH, for example), hence decreasing the defences against the oxidative stress.
The present analysis is able to explain the ubiquitous effect of reinforcement of the biological effects of the dose when the combination of ionising radiation in presence of high-Z atoms is considered. We hope that these considerations will be useful to the researchers trying to improve the therapeutic index of the ion therapy.