Improving proton therapy by metal-containing nanoparticles:Nanoscale insights

The use of nanoparticles to enhance the effect of radiation-based cancer treatments is a growing field of study and recently, even nanoparticle-induced improvement of proton therapy performance has been investigated. Aiming at a clinical implementation of this approach, it is essential to characterize the mechanisms underlying the synergistic effects of nanoparticles combined with proton irradiation. In this study, we investigated the effect of platinum- and gadolinium-based nanoparticles on the nanoscale damage induced by a proton beam of therapeutically relevant energy (150 MeV) using plasmid DNA molecular probe. Two conditions of irradiation (0.44 and 3.6 keV/mu m) were considered to mimic the beam properties at the entrance and at the end of the proton track. We demonstrate that the two metal-containing nanoparticles amplify, in particular, the induction of nanosize damages (&gt;2 nm) which are most lethal for cells. More importantly, this effect is even more pronounced at the end of the proton track. This work gives a new insight into the underlying mechanisms on the nanoscale and indicates that the addition of metal-based nanoparticles is a promising strategy not only to increase the cell killing action of fast protons, but also to improve tumor targeting.</p

Challenges and Contradictions of Metal Nano-Particle Applications for Radio-Sensitivity Enhancement in Cancer Therapy

From the very beginnings of radiotherapy, a crucial question persists with how to target the radiation effectiveness into the tumor while preserving surrounding tissues as undamaged as possible. One promising approach is to selectively pre-sensitize tumor cells by metallic nanoparticles. However, though the “physics” behind nanoparticle-mediated radio-interaction has been well elaborated, practical applications in medicine remain challenging and often disappointing because of limited knowledge on biological mechanisms leading to cell damage enhancement and eventually cell death. In the present study, we analyzed the influence of different nanoparticle materials (platinum (Pt), and gold (Au)), cancer cell types (HeLa, U87, and SKBr3), and doses (up to 4 Gy) of low-Linear Energy Transfer (LET) ionizing radiation (- and X-rays) on the extent, complexity and reparability of radiation-induced H2AX + 53BP1 foci, the markers of double stand breaks (DSBs). Firstly, we sensitively compared the focus presence in nuclei during a long period of time post-irradiation (24 h) in spatially (three-dimensionally, 3D) fixed cells incubated and non-incubated with Pt nanoparticles by means of high-resolution immunofluorescence confocal microscopy. The data were compared with our preliminary results obtained for Au nanoparticles and recently published results for gadolinium (Gd) nanoparticles of approximately the same size (2–3 nm). Next, we introduced a novel super-resolution approach—single molecule localization microscopy (SMLM)—to study the internal structure of the repair foci. In these experiments, 10 nm Au nanoparticles were used that could be also visualized by SMLM. Altogether, the data show that different nanoparticles may or may not enhance radiation damage to DNA, so multi-parameter effects have to be considered to better interpret the radiosensitization. Based on these findings, we discussed on conclusions and contradictions related to the effectiveness and presumptive mechanisms of the cell radiosensitization by nanoparticles. We also demonstrate that SMLM offers new perspectives to study internal structures of repair foci with the goal to better evaluate potential differences in DNA damage patterns

AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine

International audienceAGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Improvement of hadrontherapy by addition of nanoparticles

Le cancer est l'une des principales causes de décès dans le monde, trouver des traitements plus efficaces est donc d’un intérêt majeur. La radiothérapie conventionnelle utilisant des rayons X peut détruire des tumeurs, mais provoque des effets secondaires nocifs pour les tissus sains environnants. L'hadronthérapie est un outil utilisant des ions pour irradier la tumeur et qui s’avère très efficace pour le traitement du cancer. Les propriétés physiques particulières des ions permettent de mieux cibler et donc d’irradier un volume bien défini comme la tumeur. Afin de renforcer le ciblage et l'efficacité des traitements, une amplification de la mort cellulaire spécifiquement dans la tumeur est nécessaire. Pour améliorer les traitements, nous proposons une stratégie innovante qui combine des nano-médicaments et l'irradiation par des ions rapides.Nous avons déjà montré que les sels de platine renforcent fortement l’endommagement à l'ADN induit par les différentes irradiations (telles que les rayons X et les ions rapides) et accélèrent la mort des cellules. Cet effet est attribué à l'ionisation des électrons du platine en couche interne par les électrons produits le long de la trace, suivi par la désexcitation Auger du métal. Ces électrons Auger peuvent induire des dommages de façon directe ou par effet indirect via les radicaux produits dans l’eau. Le défi est de déposer ces sensibilisateurs dans la tumeur. Les développements récents en matière de nanotechnologie apportent de nouvelles perspectives par l’utilisation de nanoparticules, qui peuvent être fonctionnalisées afin de cibler des tissus spécifiques.Notre étude montre que l'irradiation avec des ions carbone provenant du HIMAC (centre médical Japonais, leader en hadronthérapie) en présence de ces nanoparticules induit une augmentation significative des dommages à l'ADN. En particulier, notre travail permet de comprendre que cette combinaison induit des dommages plus complexes que lorsque les sels de platine sont utilisés. Cet effet est expliqué par l'auto-amplification des cascades d'électrons Auger à l'intérieur des nanoparticules. Des radicaux de l'eau sont produits à l'échelle de l’ADN et conduisent à son endommagement. Cette amplification des dommages a été observée dans les cellules vivantes en présence de nanoparticules bien qu’elles se trouvent exclusivement dans le cytoplasme. L’amplification des dommages décrite pour l’ADN peut avoir lieu dans n'importe quelle molécule contenue dans le cytoplasme ce qui peut mener à la destruction d’organites.Ce travail à l'interface de la physique, de la chimie et de la biologie présente un fort intérêt pour l'élaboration de protocoles médicaux tels que l'hadronthérapie et la nanomédecine, ceci afin d’améliorer l'efficacité et la précision des traitements.Cancer is one of the major causes of death in the world, finding more effective treatments is therefore of major interest. Conventional radiotherapy using X-rays can destroy tumors but causes harmful side effects to surrounding healthy tissues. The hadrontherapy is a powerful tool for cancer treatment which uses ions to irradiate the tumor. The particular physical properties of ions allow better targeting, and therefore, an irradiation of the well-defined volume of the tumor. In order to further enhance the targeting and the efficiency of the treatments, an amplification of the cell death rate specifically in the tumor is of strong interest. To improve treatments, we propose an innovative strategy that combines nano-drugs and irradiation by fast ions.We already showed that platinum salts enhance strongly DNA damage induced by different radiations (such as X-rays and fast ions) and accelerate cell death. This effect is attributed to the ionization of inner shell electrons of platinum by the electrons produced along the track, followed by Auger de-excitation of the metal. These Auger electrons can induce damage by direct or indirect effect (water radicals mediated). The challenge is to locate these sensitizers in the tumor. Recent developments in nanotechnology pointed out new perspectives by using nanoparticles, which can be functionalized to target specific tissues.Our study shows that irradiation with carbon ions from HIMAC (Japanese medical center, leader in hadrontherapy) in presence of these nanoparticles induces a significant increase of DNA damage. In particular, our work helps to understand that this combination induces more complex lethal damage compared to platinum salts. This effect is explained by the auto-amplification of Auger electron cascades inside the nanoparticles. Numerous water radicals are produced at DNA scale leading to its damage. Same observation of damage amplification has been made in living cells loaded with nanoparticles while they stay exclusively in the cytoplasm. The amplification of damage described on DNA can occur in a cytoplasm included molecule and may induce organelle destruction.This work at the interface of physics, chemistry and biology finds strong interest for developing medical protocols such as hadrontherapy and nanomedicine improving effectiveness and accuracy of treatment

Utilisation des nanoparticules pour ameliorer les performances de la hadrontherapie

Le cancer est l'une des principales causes de décès dans le monde, trouver des traitements plus efficaces est donc d un intérêt majeur. La radiothérapie conventionnelle utilisant des rayons X peut détruire des tumeurs, mais provoque des effets secondaires nocifs pour les tissus sains environnants. L'hadronthérapie est un outil utilisant des ions pour irradier la tumeur et qui s avère très efficace pour le traitement du cancer. Les propriétés physiques particulières des ions permettent de mieux cibler et donc d irradier un volume bien défini comme la tumeur. Afin de renforcer le ciblage et l'efficacité des traitements, une amplification de la mort cellulaire spécifiquement dans la tumeur est nécessaire. Pour améliorer les traitements, nous proposons une stratégie innovante qui combine des nano-médicaments et l'irradiation par des ions rapides.Nous avons déjà montré que les sels de platine renforcent fortement l endommagement à l'ADN induit par les différentes irradiations (telles que les rayons X et les ions rapides) et accélèrent la mort des cellules. Cet effet est attribué à l'ionisation des électrons du platine en couche interne par les électrons produits le long de la trace, suivi par la désexcitation Auger du métal. Ces électrons Auger peuvent induire des dommages de façon directe ou par effet indirect via les radicaux produits dans l eau. Le défi est de déposer ces sensibilisateurs dans la tumeur. Les développements récents en matière de nanotechnologie apportent de nouvelles perspectives par l utilisation de nanoparticules, qui peuvent être fonctionnalisées afin de cibler des tissus spécifiques.Notre étude montre que l'irradiation avec des ions carbone provenant du HIMAC (centre médical Japonais, leader en hadronthérapie) en présence de ces nanoparticules induit une augmentation significative des dommages à l'ADN. En particulier, notre travail permet de comprendre que cette combinaison induit des dommages plus complexes que lorsque les sels de platine sont utilisés. Cet effet est expliqué par l'auto-amplification des cascades d'électrons Auger à l'intérieur des nanoparticules. Des radicaux de l'eau sont produits à l'échelle de l ADN et conduisent à son endommagement. Cette amplification des dommages a été observée dans les cellules vivantes en présence de nanoparticules bien qu elles se trouvent exclusivement dans le cytoplasme. L amplification des dommages décrite pour l ADN peut avoir lieu dans n'importe quelle molécule contenue dans le cytoplasme ce qui peut mener à la destruction d organites.Ce travail à l'interface de la physique, de la chimie et de la biologie présente un fort intérêt pour l'élaboration de protocoles médicaux tels que l'hadronthérapie et la nanomédecine, ceci afin d améliorer l'efficacité et la précision des traitements.Cancer is one of the major causes of death in the world, finding more effective treatments is therefore of major interest. Conventional radiotherapy using X-rays can destroy tumors but causes harmful side effects to surrounding healthy tissues. The hadrontherapy is a powerful tool for cancer treatment which uses ions to irradiate the tumor. The particular physical properties of ions allow better targeting, and therefore, an irradiation of the well-defined volume of the tumor. In order to further enhance the targeting and the efficiency of the treatments, an amplification of the cell death rate specifically in the tumor is of strong interest. To improve treatments, we propose an innovative strategy that combines nano-drugs and irradiation by fast ions.We already showed that platinum salts enhance strongly DNA damage induced by different radiations (such as X-rays and fast ions) and accelerate cell death. This effect is attributed to the ionization of inner shell electrons of platinum by the electrons produced along the track, followed by Auger de-excitation of the metal. These Auger electrons can induce damage by direct or indirect effect (water radicals mediated). The challenge is to locate these sensitizers in the tumor. Recent developments in nanotechnology pointed out new perspectives by using nanoparticles, which can be functionalized to target specific tissues.Our study shows that irradiation with carbon ions from HIMAC (Japanese medical center, leader in hadrontherapy) in presence of these nanoparticles induces a significant increase of DNA damage. In particular, our work helps to understand that this combination induces more complex lethal damage compared to platinum salts. This effect is explained by the auto-amplification of Auger electron cascades inside the nanoparticles. Numerous water radicals are produced at DNA scale leading to its damage. Same observation of damage amplification has been made in living cells loaded with nanoparticles while they stay exclusively in the cytoplasm. The amplification of damage described on DNA can occur in a cytoplasm included molecule and may induce organelle destruction.This work at the interface of physics, chemistry and biology finds strong interest for developing medical protocols such as hadrontherapy and nanomedicine improving effectiveness and accuracy of treatment.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Particle therapy and nanomedicine: state of art and research perspectives

Abstract Cancer radiation therapy with charged particle beams, called particle therapy, is a new therapeutic treatment presenting major advantages when compared to conventional radiotherapy. Because ions have specific ballistic properties and a higher biological effectiveness, they are superior to x-rays. Numerous medical centres are starting in the world using mostly protons but also carbon ions as medical beams. Several investigations are attempting to reduce the cost/benefit ratio and enlarge the range of therapeutic indications. A major limitation of particle therapy is the presence of low but significant damage induced in healthy tissues located at the entrance of the ion track prior to reaching the tumour. It is thus a major challenge to improve the targeting of the tumours, concentrating radiation effects in the malignance. A novel strategy, based on the addition of nanoparticles targeting the tumour, was suggested over a decade ago to improve the performance of conventional photon therapy. Recently, similar developments have emerged for particle therapy and the amount of research is now exploding. In this paper, we review the experimental results, as well as theoretical and simulation studies that shed light in the promising outcomes of this strategy and in the underpinning mechanisms. Several experiments provide consistent evidence of significant enhancement of ion radiation effects in the presence of nanoparticles. In view of implementing this strategy for cancer treatment, simulation studies have begun to establish the rationale and the specificity of this effect. In addition, these studies will help to outline a list of possible mechanisms and to predict the impact of ion beams and nanoparticle characteristics. Many questions remain unsolved, but the findings of these first studies are encouraging and open new challenges. After summarizing the main results in the field, we propose a roadmap to pursue future research with the aim to strengthen the potential interplay between particle therapy and nanomedicine

radiochimie et chimie sous rayonnement vivant et santéComprendre et améliorer les effets cliniques de la hadronthérapie

International audienceCharged particles beams allowed to improve targeting and effectiveness of radiotherapy treatments. On the onehand, it reduces toxicities induced in the sensitive organs. On the other hand, it increases local control, in particularof radioresistant cancers. Better knowledge of the effects of linear energy transfer (LET), particularly at the Braggpeak, and of water radiolysis have advanced this treatment method. However, many scientific and technicalobstacles still need to be resolved to move towards personalized particle therapy (hadrontherapy) treatments.For example, the effectiveness of treatments can be further improved by associating nanoparticles with elevatedLET radiations. The current research ranges from particles physics and fundamental chemistry to clinical trialsinvolving different research teams worldwide.L’utilisation des faisceaux de particules chargées a amélioré à la fois la sélectivité et l’efficacité des traitements deradiothérapie. Ceux-ci permettent de réduire les toxicités induites dans les organes sensibles, et d’autre partd’augmenter le contrôle local des tumeurs, notamment au niveau des tumeurs radiorésistantes. De meilleuresconnaissances des effets du transfert d’énergie linéique (TEL), principalement au niveau du pic de Bragg, et de laradiolyse de l’eau ont fait progresser cette méthode de traitement. Cependant, de nombreux verrous scientifiqueset techniques doivent encore être levés pour aller vers des traitements de hadronthérapie plus personnalisés. Parexemple, l’efficacité thérapeutique peut encore être améliorée en associant l’utilisation de nanoparticulesmétalliques à celle de rayonnements de TEL élevé. Les domaines de recherche concernés vont de la physiquedes particules et la chimie fondamentale jusqu’aux essais cliniques, impliquant différentes communautés dechercheurs à l’international