Abstract
A recent paper (Kim et al 2010 Nanotechnology 21 425102) presented results on the combination of irradiation by atomic ions of cells loaded by particles made of heavy atoms. They propose that the projectile induced x-rays emission (PIXE) mechanism has an important contribution to the enhancement of the cell death rate.
Experiments made in our group to study the effects of such a combination have shown that the Auger effect induced in the high-Z atoms and the following induction of surrounding water radiolysis has an important contribution to the enhancement of the cell death rate.
In the light of our studies we propose an alternative interpretation of the results presented in the paper by Kim et al.
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The paper of Kim et al [1] reports a decrease of cell survival and tumor growth when the cells are loaded with gold or iron nanoparticles and irradiated with 45 MeV protons. The results are interesting and show the potential of such a strategy for improving cancer therapy using fast ions, as we have already proposed in different papers quoted in the references. However, the interpretation of Kim's results is misleading. This would have been less hazardous if there had been the correct documentation for this rapidly developing topic (see, e.g., [7]).
As already demonstrated by Dollinger in his comment, the mechanism proposed, the excitation with high-Z atoms followed by the emission of x-rays (PIXE), does not play any significant role in the cell death induction [2].
Our group has long experience in the study of the combined effect of high-Z radiosensitizers (molecules or nanoparticles) and ionizing radiation involving x-rays at the Photon Factory (Tsukuba, Japan) or fast ions at the Heavy Ion Medical Accelerator (HIMAC, Chiba, Japan) [3–10]. Studies of the DNA damage (and respective cell death rate) must be systematically compared in the presence or absence of sensitizers.
In all of our experiments—carried out with or without heavy atoms—we have observed that in the presence of a free radical scavenger, like dimethylsulfoxide (DMSO), the radiation effects decrease strongly. This shows that the major part of the mechanism is free radical mediated. This was not explored by Kim et al.
To explain these findings, we have proposed the following mechanisms for interpreting the enhancement of the radiation-induced biological damage by radiosensitizers. This interpretation is based on several experiments including the resonant photoabsorption of x-rays and radiation experiments with atomic ions—helium He2+, C6+, Fe26+—with linear energy transfers (LET) ranging from 2 up to 500 keV μm−1 [3–7, 9]. The interaction of the incident ionizing particles with the biological matter induces ionization of the biological medium, due to Compton or photoelectric effects when gamma rays or x-rays are used or to the stopping power of the atomic ions. The electrons emitted along the primary tracks are able to induce inner shell ionization of the heavy atom. The relaxation of the excited core takes place by Auger excitation mainly. The contribution of the radiative channel (fluorescence) is minor. Direct excitation of the heavy atom by the incident atomic ion is also possible, but the probability of such a mechanism was found to be small. In a second step, the Auger electrons emitted from the high-Z sensitizer induce the radiolysis of the surrounding water and the production of free radical clusters, in particular of highly oxidizing free hydroxyl radicals, HO°. These radicals induce molecular damage by free radical attacks or cell death due to a large oxidative stress. One major result presented in [6] is that the sensitizers do not need to be in the cell nucleus to trigger a significant cell death enhancement. In conclusion, there is no enhancement of the energy deposition by the incident particles but a conversion of the energy of the secondary electrons (along the track) into the energy of Auger electrons emitted by the high-Z atoms and production of ROS in a nanometric volume. Finally, the concept of 'dose enhancement or reinforcement of dose', commonly used, is a little bit misleading. One should speak about 'enhancement of the dose effect' instead. The latter concept is related to the familiar relative biology efficiency.
One cannot exclude the possibility, in particular in experiments involving gold, that a pharmacological effect exists. Gold atoms can be in different oxidation states following irradiation and might migrate through the cytoplasm and react with the thiols (glutathione GSH for example). This will decrease the defences against oxidative stress.
The present analysis is able to interpret the ubiquitous effect of reinforcement of the biological effects of the dose when the combination of ionizing radiation plus high-Z atoms is considered. We hope that these considerations will be useful to researchers trying to improve the therapeutic index of the ion therapy.