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It offers the reader an opportunity to learn from a coherent approach about the physics, chemistry and biology relevant to ion-beam cancer therapy, a growing field of important medical application worldwide. The book describes phenomena occurring on different time and energy scales relevant to the radiation damage of biological targets and ion-beam cancer therapy from the molecular nano scale up to the macroscopic level.

It illustrates how ion-beam therapy offers the possibility of excellent dose localization for treatment of malignant tumours, minimizing radiation damage in normal tissue whilst maximizing cell-killing within the tumour, offering a significant development in cancer therapy. The full potential of such therapy can only be realized by better understanding the physical, chemical and biological mechanisms, on a range of time and space scales that lead to cell death under ion irradiation. This book describes how, using a multiscale approach, experimental and theoretical expertise available can lead to greater insight at the nanoscopic and molecular level into radiation damage of biological targets induced by ion impact.

The book is intended for advanced students and specialists in the areas of physics, chemistry, biology and medicine related to ion-beam therapy, radiation protection, biophysics, radiation nanophysics and chemistry, atomic and molecular physics, condensed matter physics, and the physics of interaction of charged particles with matter.

One of the most important features of the book is the inclusive multiscale approach to the understanding of complex and highly interdisciplinary processes behind ion-beam cancer therapy, which stretches from the atomistic level up to the biological scale and is demonstrated to be in excellent agreement with experimental observations. 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. 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.

Based on the properties of high-energy photons to traverse the entire body, this non-invasive method is used to treat deeply seated tumours. However, as the interaction of photons is not tissue specific, severe side effects or even secondary cancers may be induced when healthy tissues are damaged. It is thus a major challenge to develop new strategies and improve the tumour selectivity of radiation effects. The enrichment of tumours with high-Z compounds has been proposed as a new strategy to improve the effects of radiation as due to the amplification of primary electronic processes.

To avoid confusion with radiosensitizing drugs, those compounds that make cells more sensitive to radiation, such as DNA repair inhibitors, oxygen transporters [see for instance Lawrence et al. The principle of radio-enhancement was first demonstrated using metallic complexes to increase the effects of high-energy photons [see Kobayashi et al. The clinical use of these compounds is, however, limited by the lack of tumour selectivity. Hence, nanoparticles NPs have been proposed as a more efficient means to improve the concentration of active products in the tumour and, as a consequence, to improve the tumour targeting of radiation effects.

Tumour targeting may also be achieved when nanoparticles are functionalized with tumour specific agents such as antibodies or other peptides [see Friedman et al. Thus, the combination of radiation therapies with nanomedicine opens a new range of treatments Kong et al. Hainfeld et al. Gold NPs are presently the most well studied agents [see Her et al. Other sophisticated NPs, composed of other heavy elements such as hafnium Maggiorella et al.

Although conventional radiotherapy has been tremendously improved e. The latter are mainly related to the geometry of the irradiation e. Moreover, conventional radiotherapy is not able to eradicate rare but highly aggressive radioresistant cancers such as glioblastoma and chordoma, for which the treatment outcomes remain poor. For these cases, treatment by high-energy ions such as protons proton therapy and carbon ions carbon therapy is being proposed as an alternative Durante et al.

Thus, the beam may be tuned by modulating its energy to target the tumour without damaging the tissues located at a deeper position [see Fig. Moreover, thanks to a larger relative biological effectiveness RBE associated to ion beam radiation as compared to X-rays due to its more densely ionizing feature providing greater cell killing for the same amount of delivered dose Scifoni , particle therapy is also the most efficient method to treat radioresistant tumours Ares et al.

Carbon ions in particular can, in some cases, be four times more efficient than X-rays Loeffler and Durante ; Kamada et al. Particle therapy is thus considered, at least for a number of indications, superior to conventional radiotherapy Baumann et al. In fact, beyond the 74 centres already in operation as of April , 83 new centres have already started construction [e. Illustration of a highly penetrating X-ray radiation propagation leading to damage in healthy tissues, b ballistic effects of ions with negligible radiation effects after the tumour but still significant effects at the entrance of the track, and c improvement of ion radiation effects in the tumour in the presence of nanoparticles, which opens the possibility to reduce the dose to the patient and the dose deposition in the tissues located prior to reaching the tumour.

Particle therapy is delivered with two different modalities. One is the passively modulated broad beam modality, which consists of a beam shaped to the target with a spread out Bragg peak SOBP.

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The second is the recent pencil beam active scanning mode, where a beamlet of a few mm is scanned, spot by spot, on the tumour, modulating the energy for each depth slice Schardt et al. Because of its larger degradation of the beam through the beamline materials, the broad beam modality usually provides a larger entrance channel dose, as compared to the pencil beam Shiomi et al. Hence, because of the physical profile of the beam, a low but significant dose deposited by the ions in the tissues located before reaching the tumour [see Fig.

Moreover, damage to surrounding tissues may be caused by motion and a range of other uncertainties. To overcome these limitations, the addition of NREs to the tumour is proposed as a challenging strategy to amplify the effect of ion radiation locally and thus reduce the total dose to the patient. The use of contrast agents, in particular, offers the possibility to follow the biodistribution of the agent as well as to image the tumour just prior to or during the treatment.

Biophysics Modeling to Optimize Ion Beam Cancer Therapy

While nanomedicine is now approaching a clinical stage in conventional radiotherapy, only few studies have been dedicated to the combination of high-Z NREs with ion beam modalities. This review summarizes the first experimental and modelling studies that display and tentatively describe the effects of different radio-enhancers, including metallic complexes and NPs, used to improve the performance of particle beam treatments, e. The first section exposes the major results reported on the effects of i platinum complexes activated by different ion radiations helium, carbon, iron , ii gold NPs combined with proton radiation and iii platinum NPs and gadolinium-based nanoagents AGuiX combined with carbon radiation.

In the second section, the recent modelling and simulation studies dedicated to radio-enhancement induced by ion radiation are collected together with a summary of the known results and the remaining open questions to be faced. The proof of principle of this strategy was first demonstrated with platinum complexes chloroterpyridine platinum, PtTC used as radio-enhancers presented below.

Given that nanosize bio-damage is the most lethal for living cells, the amplification of these types of damage is a major challenge of the strategy.


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Hence, DNA plasmids have been used as nano-bioprobes to detect and quantify the induction of nanosize bio-damage. The study of Usami et al. Thus, the amplification of ion radiation by high-Z agents was explained by i the activation of the high-Z atoms by incident ions or electrons of the track due to Coulombic interaction, ii de-excitation and electron emission and iii production of radicals in the medium.

Here again, the important role of water radicals was demonstrated. Interestingly, the radio-enhancement effect was found to be lower with high LET iron ions. This was attributed to a decrease of the indirect effect due to an overproduction of hydroxyl radicals that recombine and produce peroxide Hirayama et al. These molecular scale experiments were followed by cellular scale proof of principle studies.

The effect of the efficacy of the same platinum complexes chloroterpyridine platinum to amplify the effects of carbon ions was shown in vitro Usami et al. This study confirmed that hydroxyl radicals play a major role. Interestingly, it was found that the enhancement efficacy per track is larger at the track end high LET , while from simple mechanistic arguments one would expect the contrary, i. More importantly, microscopy measurements demonstrated, for the first time, that cell killing is enhanced despite the localization of the radio-enhancing agents in the cytoplasm, and not in the nucleus, of the cells see Fig.

This was a major outcome, which already showed that radio-enhancement by high-Z agents activated by ionizing radiation begins in the cell cytoplasm see Fig. The darker areas correspond to the cell nucleus. Adapted from Usami et al. Adapted from Porcel et al. These studies opened the perspectives to improve the performance of particle therapy using high-Z complexes.

They shed light on putative early stage mechanisms involved in the enhancement of radiation effects, and on the role of hydroxyl radicals in particular. Unfortunately, these complexes, which are not tumour specific and not detectable by medical imaging CT and MRI , are not suitable for clinical transfer.

As an alternative, nanotechnologies open new perspectives to target tumours. The effect of nanoparticles, combined with particle radiation, has been probed with high-energy protons and medical carbon ions see below. The effectiveness of high-Z nanoparticles to improve the performance of proton radiation was first demonstrated by Kim et al. They observed that small nanoparticles diameter 1.

They also observed, with in vitro experiments, that cell killing is enhanced when CT 26 cells are loaded with nanoparticles. Thus, the group demonstrated that in vivo impact is strongly correlated with increasing cell killing. This shows the impact of cellular scale effects on the body scale impact.

The mechanism proposed by the authors has proven to be controversial. It was argued that proton induced X-ray emission PIXE cannot account as the major process in the amplification of radiation effects Dollinger Indeed, the probability for the nanoparticles to be activated by the X-rays induced by PIXE was proved to be very low, as explained in detail by Dollinger The efficiency of gold to enhance the effects of proton radiation was confirmed in vitro by Polf et al. Kim et al. This finding is in full agreement with the conclusion of the above-mentioned studies using platinum complexes.

Jeynes et al. However, Li et al. Surprisingly, the nanoparticles were found located in the nucleus, unlike most other studies using gold nanoparticles [see Moser et al. They highlighted the important role of hydroxyl radicals. Here again, the role of hydroxyl radicals was shown. More importantly, the radio-enhancement effect was found to be greater at the end of the ion track. In summary, these studies reinforce the perspective of using NREs to concentrate the effects of proton radiation at the track end in the tumours.

The group of Lacombe Porcel et al. Here again, the role of ROS in the amplification of nanosize bio-damage was highlighted. As mentioned in more detail in the next section on the mechanistic analysis, nanoparticles may be activated by charged particles incident ions or secondary electrons of the track by Coulombic interaction including ionization and surface plasmon excitation channels.

Radicals are produced due to the interaction of electrons emitted by the nanoparticles, but also by the capture of electrons from surrounding water molecules. Interestingly, a significant role of the nanoparticle structure was observed, and metallic nanoparticles were found to be more efficient than metallic complexes at the same concentration. This was attributed to the size of the volume perturbed by the radio-enhancers which, in the case of nanoparticles, is of the order of a few nanometers.

The emission of electrons and consecutive ROS clusters produced in this nano-volume can favour the induction of complex damage. In contrast, molecular agents amplify the electron emission in smaller volumes, which is less efficient to induce molecular damage of nanometer size.

Hence, nanoparticles do not merely increase the number of breaks but rather improve the quality of the radiation effect. The biological response to this early stage nanoscale perturbation may be diverse and is the subject of several cell studies. Kaur et al. The authors obtained a higher effect than the one observed with the proton beam irradiation observed by Polf et al. However, since the groups used different cell models, cell uptake and cell sensitivity may well play an important role.

The amplification of medical carbon radiation effects was then evidenced with gadolinium-based nanoagents AGuiX from Nano-H, Lyon, France. These theranostic agent have unique multimodal properties, including improvement of MRI contrast and enhancement of radiation effects Porcel et al. The relationships between cellular and molecular impacts and the role of ROS were also shown. Noticeably, the gadolinium-based nanoparticles were found located in the cytoplasm [see Fig.

This study opened the first opportunity to introduce theranostic in carbon therapy. They established that the enhancement does not increase with the concentration of nanoparticles, which indicates that this effect is not related to the physical dose. This confirms the conclusion of Porcel et al. Here again, the nanoparticles were found located in the cytoplasm.

Chronological overview of experimental studies on radio-enhancement of fast ion radiation effects by high-Z compounds. Studies at molecular scale black , in vitro blue and in vivo red levels are reported. The method of LET measurements are not specified in the papers, but are usually determined on the basis of measurements performed with ionization chambers in water. The absence of ticks is indicating the absence of data. About us How to find us dr. Faculty of Science and Engineering. Research Research units: Quantum interactions and structural dynamics.

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