3 research outputs found
Effet de lâoxygĂšne dans l'irradiation par des ions mĂ©dicaux combinĂ©s avec des nanoparticules
About 50% of the cancer patients who are treated benefit from radiation therapy. Conventional radiotherapy consists of high energy X-rays traveling through the tissues, so that deeply sited tumors are treated in a non-invasive way. Unfortunately, X-rays are not tumor selective and healthy tissues may be damaged. This lack of selectivity is responsible for severe side effects and/or secondary cancers. Hence, improving the differential of radiation effects between the tumor and surrounding tissues remains a major challenge. Particle therapy (treatment by protons or carbon ion beams) is considered as one of the most promising technique because, by opposition to X-rays, the energy deposition of ions is maximum at the end of their tracks. When the beam is tuned so that the maximum reaches the tumor, there is no damage induced in tissues siting after the tumor. Another important added value is that heavy ions are more efficient to treat radioresistant tumors. The use of this modality is however restricted by the low but significant damage that is induced to normal tissues located at the entrance of the track prior to reaching the tumor. To improve the performance of particle therapy, a new strategy based on the combination of high-Z nanoparticles with ion beam radiation has been developed by the group at ISMO. This approach aims at using nano-agents not only to increase radiation effects in the tumor but also to improve medical imaging with the same agent (theranostic). Nanoparticles present a remarkable surface chemistry, which allows functionalization with ligands able to improve biocompatibility, stability as well as blood circulation and accumulation in tumors. The group already demonstrated the efficiency of small (â 3 nm) gold and platinum nanoparticles to amplify the effects of medical carbon ions in normoxic conditions (in the presence of oxygen). However, radioresistant tumors may host hypoxic regions. It is thus urgent to quantify and characterize the influence of oxygen on the radio-enhancement effect. The goal of my thesis was to study the influence of oxygen on medical ion radiation effects in the presence of gold and platinum nanoparticles. This was performed using two radioresistant human cancer cell lines: HeLa (uterine cervix) and BxPC-3 (pancreas). Different radiation modalities were used: carbon and helium ion beams delivered by a passive scattering delivery system and carbon ion beams delivered by a pencil beam scanning system. The major results of this work are the following. In oxic conditions (Oâ concentration = 20%), an enhancement of ion radiation effects was observed for the two nanoparticles (at the same concentration in metal). This effect decreased with the oxygen concentration but remained significant for a concentration of 0.5%. No significant difference was found between the cell lines. Interestingly, the oxygen-dependence varied with the type of radiation. An attempt to explain the effect of oxygen by molecular processes is proposed. Perspectives of further developments are suggested.Environ 50% des patients recevant un traitement contre le cancer bĂ©nĂ©ficient de la radiothĂ©rapie. La radiothĂ©rapie conventionnelle consiste Ă utiliser des rayons X de haute Ă©nergie capables de traverser les tissus et de traiter des tumeurs situĂ©es en profondeur de façon non-invasive. Malheureusement, les rayons X ne font pas la distinction entre les tumeurs et les tissus sains, qui peuvent donc ĂȘtre endommagĂ©s. Cette non-sĂ©lectivitĂ© est Ă lâorigine de graves effets secondaires, voire du dĂ©veloppement de cancers secondaires. Par consĂ©quent, lâamplification des effets radiatifs au sein de la tumeur par rapport aux tissus environnants reprĂ©sente un dĂ©fi majeur.LâhadronthĂ©rapie (traitement par faisceaux de protons ou dâions carbone) est considĂ©rĂ©e comme lâune des techniques les plus prometteuses car, contrairement aux rayons X, la quantitĂ© dâĂ©nergie dĂ©posĂ©e atteint son maximum en fin de trajectoire. Lorsque le faisceau est rĂ©glĂ© de maniĂšre Ă ce que ce maximum atteigne la tumeur, aucun dommage nâest causĂ© aux tissus situĂ©s au-delĂ . Un autre avantage majeur est que les ions lourds sont plus efficaces pour traiter les tumeurs radiorĂ©sistantes. Lâutilisation de cette technique est cependant restreinte du fait des dommages â plus faibles mais nĂ©anmoins significatifs â causĂ©s aux tissus normaux situĂ©s sur la trajectoire du faisceau dâions en amont de la tumeur. Afin dâamĂ©liorer les performances de lâhadronthĂ©rapie, lâĂ©quipe a dĂ©veloppĂ© Ă lâISMO une nouvelle stratĂ©gie combinant lâutilisation de nanoparticules (NPs) mĂ©talliques avec lâirradiation par faisceaux dâions. Lâutilisation de NPs a pour but non seulement dâamplifier les effets des rayonnements dans la tumeur mais Ă©galement dâamĂ©liorer l'imagerie mĂ©dicale Ă lâaide des mĂȘmes agents (thĂ©ranostic). Les NPs possĂšdent une chimie de surface permettant leur fonctionnalisation avec des ligands capable dâamĂ©liorer la biocompatibilitĂ©, la stabilitĂ© ainsi que la circulation sanguine et lâaccumulation dans la tumeur. LâĂ©quipe a dĂ©jĂ dĂ©montrĂ© que les petites NPs dâor et de platine (â 3 nm) avaient la capacitĂ© dâamplifier les effets causĂ©s par les faisceaux dâions carbone mĂ©dicaux en prĂ©sence dâoxygĂšne. Cependant, les tumeurs radiorĂ©sistantes sont susceptibles de contenir des rĂ©gions hypoxiques. Il est donc urgent de quantifier et de caractĂ©riser lâinfluence de lâoxygĂšne sur lâeffet radio-amplificateur. Le but de ma thĂšse Ă©tait dâĂ©tudier lâinfluence de lâoxygĂšne lors dâirradiations par des faisceaux dâions mĂ©dicaux en prĂ©sence de NPs dâor et de platine. Pour cela, deux lignes de cellules cancĂ©reuses humaines radiorĂ©sistantes ont Ă©tĂ© testĂ©es: HeLa (col de lâutĂ©rus) et BxPC-3 (pancrĂ©as). Plusieurs techniques dâirradiation ont Ă©tĂ© utilisĂ©es : des faisceaux dâions carbone et hĂ©lium gĂ©nĂ©rĂ©s par « passive scattering » et des faisceaux dâions carbone gĂ©nĂ©rĂ©s par « pencil beam scanning ». Les principaux rĂ©sultats de cette Ă©tude sont les suivants. En condition oxique (concentration dâOâ = 20%), une amplification des effets radiatifs a Ă©tĂ© observĂ©e pour les deux types de NPs (Ă concentration de mĂ©tal Ă©gale). Ce phĂ©nomĂšne se rĂ©duit Ă mesure que la concentration dâoxygĂšne diminue mais reste significatif jusquâĂ 0.5%. Aucune diffĂ©rence significative nâa Ă©tĂ© observĂ©e entre les deux lignes cellulaires. Il est intĂ©ressant de noter que la dĂ©pendance Ă lâoxygĂšne varie en fonction de la technique dâirradiation utilisĂ©e. Une tentative dâexplication de lâinfluence de lâoxygĂšne par des processus molĂ©culaires est proposĂ©e. Des perspectives de dĂ©veloppements ultĂ©rieurs sont suggĂ©rĂ©es
Human serum albumin in the presence of AGuIX nanoagents: Structure stabilisation without direct interaction
International audienceThe gadolinium-based nanoagent named AGuIX Âź is a unique radiosensitizer and contrast agent which improves the performance of radiotherapy and medical imaging. Currently tested in clinical trials, AGuIX Âź is administrated to patients via intravenous injection. The presence of nanoparticles in the blood stream may induce harmful effects due to undesired interactions with blood components. Thus, there is an emerging need to understand the impact of these nanoagents when meeting blood proteins. In this work, the influence of nanoagents on the structure and stability of the most abundant blood protein, human serum albumin, is presented. Synchrotron radiation circular dichroism showed that AGuIX Âź does not bind to the protein, even at the high ratio of 45 nanoparticles per protein at 3 mg/L. However, it increases the stability of the albumin. Isothermal thermodynamic calorimetry and fluorescence emission spectroscopy demonstrated that the effect is due to preferential hydration processes. Thus, this study confirms that intravenous injection of AGuIX Âź presents limited risks of perturbing the blood stream. In a wider view, the methodology developed in this work may be applied to rapidly evaluate the impact and risk of other nano-products that could come into contact with the bloodstream