Photo-activation Therapy with Nanoparticles : modeling at a Sub-Micrometer Level and Experimental Comparison

Une approche thérapeutique innovante utilisant l'adjonction d'éléments de numéro atomique élevé à une radiothérapie de basse énergie semble offrir une voie prometteuse pour le traitement des tumeurs cérébrales résistantes. Une telle technique est notamment développée sur la ligne médicale de l'ESRF (European Synchrotron Radiation Facility) utilisant un rayonnement monochromatique allant de 25 à 90 keV [Adam 2003, Adam 2006]. Des résultats encourageants ont été obtenus en traitant des souris cancéreuses après injection de nanoparticules d'or (AuNP) [Hainfeld 2004]. Cependant, les processus physiques et l'impact biologique issus de la photoactivation de nanoparticules sont encore aujourd'hui mal compris et ne peuvent être expliqués par des calculs de doses macroscopiques [Cho 2005, Zhang 2009]. Le but de ce travail est d'évaluer par simulation Monte Carlo l'augmentation locale de dose en présence de nanoparticules ainsi que les caractéristiques des électrons secondaires produits. Dans un premier temps, des simulations ont été réalisées en utilisant une géométrie cellulaire, de manière à comparer les données simulées aux expérimentations menées à l'ESRF. Des tests de clonogénicité ont été réalisés pour mesurer le taux de radiosensibilité des cellules pour une irradiation de 4 Gy (SER4Gy) en présence de gadolinium, pour différentes énergies d'irradiation (25 keV à 1250 keV). Ces études, expérimentales et numériques, ont permis l'évaluation de l'influence de la localisation du gadolinium au sein de la cellule et la forme de ce dernier (nanoparticules ou agent de contraste). D'autre part, une étude comparative a été menée pour caractériser le comportement d'une nanoparticule sous irradiation à une échelle nanométrique, en fonction de l'énergie de faisceau, du rayon de la nanoparticule et de l'élément lourd (or et gadolinium).An innovative approach using X-ray interactions with heavy elements seems to open a promising way of treatment for resistant cancers, such as high-grade gliomas. Such a technique is developed at the medical beam line of ESRF using monochromatic X-rays in the 25-90 keV range for the treatment of brain tumors [Adam 2003, Adam 2006]. The use of gold nanoparticles (AuNP) to treat mice bearing subcutaneous tumors led to encouraging results [Hainfeld 2004]. However, the physical processes and biological impact of the photon activation of nanoparticles are not yet well understood. The experimental results cannot be explained by macroscopic dose calculations [Cho 2005, Zhang 2009]. The aim of this work was to evaluate, at the sub-cellular level, the dose enhancement in presence of nanoparticles and the properties of the secondary electrons production using Monte Carlo simulations. In a first step, simulations were performed using cell geometry, in order to compare the simulated data to the experiments realized on the ID17 beamline of ESRF. Clonogenic assays have been performed on F98 cells to measure the “Sensitizer Enhancement Ratio” for an irradiation of 4 Gy (SER4Gy) in the presence of gadolinium, for several beam energies (25 to 80 keV). These experimental and numerical studies were done to evaluate the influence of the gadolinium location within the cell and its shape (nanoparticles or contrast agent). On the other hand, a comparative study has been performed to evaluate the behavior of a nanoparticle under irradiation at a nanometer scale. Electron spectra have been studied for two heavy elements - gold and gadolinium - and several beam energies from 25 keV to 2 MeV. Experiments have shown that gadolinium nanoparticles (GdNP) incubated during 5 h with the cells were strongly effective compared to non-incubated nanoparticles and contrast agent, for the same concentration of gadolinium. A part of radiosensitivity could possibly be explained by a biological action of GdNP on the cell cycle. Another part could be attributed to the important dose enhancement factor (DEF) calculated in the vicinity of GdNP, highlighted from two-dimension DEF maps. The DEF can reach two orders of magnitude within a few nanometers of the GdNP surface and is mainly due to high-linear energy transfer electrons (< 5 keV). By modeling the case of nanoparticles randomly distributed on the cell membrane (closest to the experimental case), we showed that a good correlation exists between the SER4Gy and the membrane DEF. On the other hand, the comparison of the two elements showed that GdNP could produce more electrons (of lower energy) than AuNP (with same mass), but that the local DEF due to AuNP was more important. Interesting results were obtained by comparing the local DEF with experimental results on plasmid DNA. However, it seems important to carry on these studies by taking into account the post-irradiation chemical processes in modeling