ALBERT

Description: The objective of this work was to study the differences in terms of early biological effects that might exist between different X-rays energies by using a mechanistic approach. To this end, radiobiological experiments exposing cell monolayers to three X-ray energies were performed in order to assess the yields of early DNA damage, in particular of double-strand breaks (DSBs). The simulation of these irradiations was set in order to understand the differences in the obtained experimental results. Hence, simulated results in terms of microdosimetric spectra and early DSB induction were analyzed and compared to the experimental data. Human umbilical vein endothelial cells (HUVECs) were irradiated with 40, 220 kVp, and 4 MV X-rays. The Geant4 Monte Carlo simulation toolkit and its extension Geant4-DNA were used for the simulations. Microdosimetric calculations aiming to determine possible differences in the variability of the energy absorbed by the irradiated cell population for those photon spectra were performed on 10,000 endothelial cell nuclei representing a cell monolayer. Nanodosimetric simulations were also carried out using a computation chain that allowed the simulation of physical, physico-chemical, and chemical stages on a single realistic endothelial cell nucleus model including both heterochromatin and euchromatin. DNA damage was scored in terms of yields of prompt DSBs per Gray (Gy) and per giga (109) base pair (Gbp) and DSB complexity was derived in order to be compared to experimental data expressed as numbers of histone variant H2AX (γ-H2AX) foci per cell. The calculated microdosimetric spread in the irradiated cell population was similar when comparing between 40 and 220 kVp X-rays and higher when comparing with 4 MV X-rays. Simulated yields of induced DSB/Gy/Gbp were found to be equivalent to those for 40 and 220 kVp but larger than those for 4 MV, resulting in a relative biological effectiveness (RBE) of 1.3. Additionally, DSB complexity was similar between the considered photon spectra. Simulated results were in good agreement with experimental data obtained by IRSN (Institut de radioprotection et de sûreté nucléaire) radiobiologists. Despite differences in photon energy, few differences were observed when comparing between 40 and 220 kVp X-rays in microdosimetric and nanodosimetric calculations. Nevertheless, variations were observed when comparing between 40/220 kVp and 4 MV X-rays. Thanks to the simulation results, these variations were able to be explained by the differences in the production of secondary electrons with energies below 10 keV.

Description: High-Z metallic nanoparticles (NPs) are new players in the therapeutic arsenal against cancer, especially radioresistant cells. Indeed, the presence of these NPs inside malignant cells is believed to enhance the effect of ionizing radiation by locally increasing the dose deposition. In this context, the potential of platinum nanoparticles (PtNPs) as radiosensitizers was investigated in two breast cancer cell lines, T47D and MDA-MB-231, showing a different radiation sensitivity. PtNPs were internalized in the two cell lines and localized in lysosomes and multivesicular bodies. Analyses of cell responses in terms of clonogenicity, survival, mortality, cell-cycle distribution, oxidative stress, and DNA double-strand breaks did not reveal any significant enhancement effect when cells were pre-exposed to PtNPs before being irradiated, as compared to radiation alone. This result is different from that reported in a previous study performed, under the same conditions, on cervical cancer HeLa cells. This shows that the efficacy of radio-enhancement is strongly cell-type-dependent. Simulation of the early stage ionization processes, taking into account the irradiation characteristics and realistic physical parameters in the biological sample, indicated that PtNPs could weakly increase the dose deposition (by 3%) in the immediate vicinity of the nanoparticles. Some features that are potentially responsible for the biological effect could not be taken into account in the simulation. Thus, chemical and biological effects could explain this discrepancy. For instance, we showed that, in these breast cancer cell lines, PtNPs exhibited ambivalent redox properties, with an antioxidant potential which could counteract the radio-enhancement effect. This work shows that the efficacy of PtNPs for enhancing radiation effects is strongly cell-dependent and that no effect is observed in the case of the breast cancer cell lines T47D and MDA-MB-231. Thus, more extensive experiments using other relevant biological models are needed in order to evaluate such combined strategies, since several clinical trials have already demonstrated the success of combining nanoagents with radiotherapy in the treatment of a range of tumor types.