Table of contents

The 1st Nano-IBCT Conference entitled 'Radiation Damage in Biomolecular Systems: Nanoscale Insights into Ion Beam Cancer Therapy' was held in Caen, France, in October 2011. The Meeting was organised in the framework of the COST Action MP1002 (Nano-IBCT) which was launched in December 2010 (http://fias.uni-frankfurt.de/nano-ibct). This action aims to promote the understanding of mechanisms and processes underlying the radiation damage of biomolecular systems at the molecular and nanoscopic level and to use the findings to improve the strategy of Ion Beam Cancer Therapy. In the hope of achieving this, participants from different disciplines were invited to represent the fields of physics, biology, medicine and chemistry, and also included those from industry and the operators of hadron therapy centres.

Ion beam therapy offers the possibility of excellent dose localization for treatment of malignant tumours, minimizing radiation damage in normal healthy tissue, while maximizing cell killing within the tumour. Several ion beam cancer therapy clinical centres are now operating in Europe and elsewhere. However, the full potential of such therapy can only be exploited by better understanding the physical, chemical and biological mechanisms that lead to cell death under ion irradiation. Considering a range of spatio-temporal scales, the proposed action therefore aims to combine the unique experimental and theoretical expertise available within Europe to acquire greater insight at the nanoscopic and molecular level into radiation damage induced by ion impact. Success in this endeavour will be both an important scientific breakthrough and give great impetus to the practical improvement of this innovative therapeutic technique. Ion therapy potentially provides an important advance in cancer therapy and the COST action MP1002 will be very significant in ensuring Europe's leadership in this field, providing the scientific background, required data and mechanistic insight which are indispensable for the optimization of this new therapy.

The conference gathered 115 participants originating from 28 countries and addressed a large number of highly relevant aspects concerning ion propagation in biological matter, the production of secondary particles along the ion tracks as electrons, holes and radicals, and their propagation in the biomolecular medium. In particular, the attack of DNA molecules and proteins by electrons and free radicals, the relative importance of direct and indirect damage processes as well as the role of the environment were discussed. Not only were fundamental mechanisms and processes elucidated, but radiobiological scale effects, multi-scale approaches and recent advances in the theoretical description of the underlying complex phenomena were also presented. Aspects linked to the energy deposition (LET), the characteristics of the Bragg peak and new techniques of dosimetry and radiolysis were highlighted. Furthermore, methods for increasing the therapy efficiency by using radio sensitizers and the state-of-the-art of defining precise patient treatment plans, identifying the clinical benefits of this type of therapy, were also addressed.

We would like to thank all participants for the lively exchange of ideas and results, thus making this conference a very fruitful event. Furthermore, we appreciate the financial support of the sponsors of this conference, in particular of the COST Action MP1002 financed by ESF. We would also like to express our thanks to all authors of these proceedings, as well as to the reviewers for their time, efforts and recommendations made during the preparation of this volume. Finally, many thanks to U G Huber for a careful proof-read of this manuscript.

We look forward to the 2nd Nano-IBCT Conference, which will be held in spring 2013.

Caen, 15 March 2012

Bernd A Huber, Christiane Malot, Alicja Domaracka and Andrey V Solov'yov

The Editors

The PDF also contains details of the Conference Committees and Sponsors and a list of participants.

All papers published in this volume of Journal of Physics: Conference Series have been peer reviewed through processes administered by the proceedings Editors. Reviews were conducted by expert referees to the professional and scientific standards expected of a proceedings journal published by IOP Publishing.

We review a multiscale approach to the physics of ion-beam cancer therapy, an approach suggested in order to understand the interplay of a large number of phenomena involved in radiation damage scenario occurring on a range of temporal, spatial, and energy scales. We briefly overview its history and present the current stage of its development. The differences of the multiscale approach from other methods of understanding and assessment of radiation damage are discussed as well as its relationship to other branches of physics, chemistry and biology.

The charge transfer process of carbon ions on biomolecular targets is analyzed with regard to the action of radiation on the biological medium. The theoretical treatment is performed in a wide collision energy range by means of ab-initio quantum chemistry molecular methods. The process has been investigated for a series of target molecules, thymine, uracil and 5-halouracil corresponding to a similar skeleton with different substituent. The charge transfer appears markedly anisotropic in the whole energy domain, and interesting specific features may be pointed out at low energies. In addition, such a study may provide information on the radio-sensitivity of the different bases with regard to ion-induced radiation damage.

Ionization and charge migration in DNA play crucial roles in mechanisms of DNA damage caused by ionizing radiation, oxidizing agents and photo-irradiation. Therefore, an evaluation of the ionization properties of the DNA bases is central to the full interpretation and understanding of the elementary reactive processes that occur at the molecular level during the initial exposure and afterwards. Ab initio quantum mechanical (QM) methods have been successful in providing highly accurate evaluations of key parameters, such as ionization energies (IE) of DNA bases. Hence, in this study, we performed high-level QM calculations to characterize the molecular energy levels and potential energy surfaces, which shed light on ionization and charge migration between DNA bases. In particular, we examined the IEs of guanine, the most easily oxidized base, isolated and embedded in base clusters, and investigated the mechanism of charge migration over two and three stacked guanines. The IE of guanine in the human telomere sequence has also been evaluated. We report a simple molecular orbital analysis to explain how modifications in the base sequence are expected to change the efficiency of the sequence as a hole trap. Finally, the application of a hybrid approach combining quantum mechanics with molecular mechanics brings an interesting discussion as to how the native aqueous DNA environment affects the IE threshold of nucleobases.

We present a theoretical description of highly charged carbon ion-induced ionization of isolated RNA-uracil molecules. A comparison between recent experimental and theoretical total cross sections is provided.

To fully understand the mechanisms of radiation damage in living tissues, a detailed knowledge of the processes occurring at the molecular level is needed. In the gas phase, most of the investigations concerning the ionization and fragmentation of biologically relevant molecular systems are performed with isolated molecules. The importance of such studies is limited to the intrinsic properties of these molecules because of the lack of a chemical environment. To probe the effect of such an environment on the behavior of small biomolecules under irradiation, the molecules (α-amino acids, adenine) were embedded into clusters. The present results, obtained with multiply charged ions, clearly indicate the protective role of the clusters since the total fragmentation yield is reduced for all systems. The surrounding molecules allow for a redistribution of the excess energy and of the charge within the cluster. In the case of adenine clusters, a new fragmentation channel is identified. Moreover, for hydrated adenine clusters, low-energy ion induced chemical reactions are observed, namely the proton transfer from the water cluster to the adenine molecule.

The use of heavy compounds to enhance radiation induced damage is a promising approach to improve the therapeutic index of radiotherapy. In order to quantify and control the effects of these radiosensitizers, it is of fundamental interest to describe the elementary processes which take place at the molecular level. Using DNA as a probe, we present a comparison of the damage induced in the presence of platinum compounds exposed to different types of ionizing radiation. We present the results obtained with gamma rays (Linear Energy Transfer (LET) = 0.2 keV.μm⁻¹), fast helium ions He²⁺ (LET = 2.3 keV.μm⁻¹) and fast carbon ions C⁶⁺ (LET = 13 keV.μm⁻¹ and LET = 110 keV.μm⁻¹). The efficiency of two different sensitizers was measured: platinum based molecules (the chloroterpyridine platinum - PtTC) and platinum nanoparticles (PtNP). These experiments show that the two sensitizers are efficiently amplifying molecular damage under photon or ion irradiation. Experiments with a radical scavenger confirmed that these damages are mediated by free radicals for more than 90%. More interestingly, the induction of complex damage, the most lethal for the cells, is amplified by a factor of 1.5 on average if platinum (PtTC and PtNP) is present. As already known, the induction of complex damages increases also with the radiation LET. So, finally, the most significant enhancement of complex damage is observed when ion radiation is combined with platinum induced sensitization.

Charge transfer cross sections in proton collisions with water dimers are calculated using an ab initio method based on molecular orbitals of the system. Results are compared with their counterpart in proton-water collisions to gauge the importance of intermolecular interactions in the cross sections.

Recent experiments on low energy electron attachment to DNA and its components in the condensed phase and in the gas phase are reviewed and analysed. From different condensed phase experiments the sensitivity of DNA towards low energy electrons is well documented and strand breaks in DNA are observed at subexcitation energies (< 3 eV) and also in ultrafast electron transfer experiments involving electrons in presolvated states. Gas phase experiments indicate that all building blocks of DNA (the nucleobases, the sugar and the phosphate moiety) undergo resonant dissociative electron attachment (DEA) in the subexcitation regime which may ultimately lead to strand breaks. From very recent gas phase experiments on an entire nucleotide it can be concluded that most strand breaks result from direct electron attachment to the DNA backbone, but also initial electron capture by the nucleobase following electron transfer to the backbone contributes.

Interactions of positively and negatively multiply charged biomolecular clusters with low-energy electrons, from ∼ 0 up to 50 eV of electron energy, were investigated in a high resolution Fourier-Transform Ion Cyclotron Resonance mass spectrometer equipped with an electrospray ionisation source. Electron-induced dissociation reactions of these clusters depend on the energy of the electrons, the size and the charge state of the cluster. The positively charged clusters [M_n+2H]²⁺ of zwitterionic betaines, M = (CH₃)₂XCH₂CO₂ (X = NCH₃ and S), do capture an electron in the low electron energy region (< 10 eV). At higher electron energies neutral evaporation from the cluster becomes competitive with Coulomb explosion. In addition, a series of singly charged fragments arise from bond cleavage reactions, including decarboxylation and CH₃ group transfer, due to the access of electronic excited states of the precursor ions. These fragmentation reactions depend on the type of betaine (X = NCH₃ or S). For the negative dianionic clusters of tryptophan [Trp₉-2H]²⁻, the important channel at low electron energies is loss of a neutral. Coulomb explosion competes from 19.8 eV and dominates at high electron energies. A small amount of [Trp₂–H–NH₃]⁻ is observed at 21.8 eV.

In this paper, we summarize our recent experimental and theoretical results on electron scattering from gaseous tetrahydrofuran (THF). Electron-impact ionization and total scattering cross sections were determined experimentally for energies between 50-5000 eV. Electron energy loss spectra were measured in the keV range using a transmission beam technique and for smaller energies (15-50 eV) with a crossed-beam apparatus. Using an optical potential method assuming the screening-corrected additivity rule, total, elastic and inelastic cross sections including dipole interactions were calculated (leV - lOkeV) in order to complement the experimental data. Elastic differential cross sections were also obtained. An empirical approximation to the inelastic angular distributions based on differential cross sections is proposed. The available integral and differential cross sections and energy loss distributions in the range 1 eV - 10 keV are combined into a table of recommended electron interaction cross sections with THF.

We explore from a theoretical perspective photoelectron spectra emitted from a Na₈ cluster irradiated by a short laser pulse. We use time-dependent density-functional theory (TDDFT) at the level of the local-density approximation (LDA). That includes a self-interaction correction (SIC) to recover the proper emission threshold. As environments are known to play an important role in irradiation dynamics, we consider the example of Na₈ deposited on a MgO(001) surface and compare it to the case of a free cluster. Anisotropy of emission is also briefly discussed.

Regarding the different protocols used for external cancer radiotherapy (X or γ rays, electron, proton or ions beams) or radioimmunotherapy (Auger electron emitting radionuclides), the initial energy deposited in integrated biological systems (biomolecular and sub-cellular targets) represents a decisive parameter for the primary and more delayed radiation damage. A short-range energy distribution governs mainly ⁱ⁾ the early survival probability of secondary electrons, ⁱⁱ⁾ the spatio-temporal distribution of short-lived reactive radicals inside nascent tracks, ⁱⁱⁱ⁾ the primary biomolecular alterations triggered by low energy secondary electrons. The thorough understanding of these fundamental processes requires a real-time investigation of primary radiation events, typically in the temporal range 10⁻¹⁴- 10⁻¹¹ s. Laser-plasma accelerators based High Energy Radiation Femtochemistry (HERF) represents a newly emerging interdisciplinary field which can be driven in strong synergy with the generation of ultrashort particle beams in the MeV energy domain. The innovating developments of HERF would favour the investigation of prethermal radiation processes in aqueous and biochemically relevant environments. In this way, the quantum character of a very-short lived low-energy electron state (p-like configuration) represents a promising sub-nanometric probe to explore early radiation processes in native tracks. The specific properties of ultra-short electron beams accelerated by TW laser are very useful for future developments of spatio-temporal radiation biophysics in complex biological systems such as living cells.

Quantification of DNA damage, induced by various types of incident radiation as well as chemical agents, has been the subject of many theoretical and experimental studies, supporting the development of modern cancer therapy. The primary observations showed that many factors can lead to damage of DNA molecules. It became clear that the development of experimental techniques for exploring this phenomenon is required. Another problem was simultaneously dealt with, anticipating on how the damage is distributed within the double helix of the DNA molecule and how the single strand break formation and accumulation can influence the lethal double strand break formation. In this work the most important probabilistic models for DNA strand breakage and damage propagation are summarized and compared.

By means of full-atom molecular dynamics simulations we investigate the process of DNA backbone damage by nanoscale shock waves in a water environment. These shock waves are created by ions penetrating the medium with high linear energy transfer. The high rate of the ions' energy transfer to the surrounding molecules leads to the rapid increase of the temperature in the vicinity of the ion trajectory, which causes the formation of shock waves propagating through the medium. We have investigated the ions' linear energy transfer of 900, 2000 and 5000 eV/nm. In the case of a linear energy transfer of 5000 eV/nm the deposition exerts unsustainable stress onthe DNA molecule, which leads to the breakage of DNA backbone covalent bonds by thermomechanical effects.

We use a simulation code, based on Molecular Dynamics and Monte Carlo, to investigate the depth-dose profile and lateral radial spreading of swift proton beams in liquid water. The stochastic nature of the projectile-target interaction is accounted for in a detailed manner by including in a consistent way fluctuations in both the energy loss due to inelastic collisions and the angular deflection from multiple elastic scattering. Depth-variation of the projectile charge-state as it slows down into the target, due to electron capture and loss processes, is also considered. By selectively switching on/off these stochastic processes in the simulation, we evaluate the contribution of each one of them to the Bragg curve. Our simulations show that the inclusion of the energy-loss straggling sizeably affects the width of the Bragg peak, whose position is mainly determined by the stopping power. The lateral spread of the beam as a function of the depth in the target is also examined.

Bragg-peak radiosurgery and proton radiography have been used in radiotherapy over the past few years. Non-Bragg-peak (plateau) relativistic protons (E>1 GeV) can offer advantages both in terms of precision and target margin reduction, and especially thanks to the possible simultaneous use of high-resolution online proton radiography. Here we will present initial simulations and experiments toward image-guided stereotactic radiosurgery using GeV protons.

Several dozen clinical sites around the world apply beams of fast light ions for radiotherapeutical purposes. Thus there is a vested interest in the various physical and radiobiological processes governing the interaction of ion beams with matter, specifically living systems. We discuss the various modelling steps which lead from basic interactions to the application in actual patient treatment planning. The nano- and microscopic scale is covered by sample calculations with our TRAX code. On the macroscopic scale we feature the TRiP98 treatment planning system, which was clinically used in GSI's radiotherapy pilot project.

Hadrontherapy is one of the most promising radiotherapeutical innovations that deal with accelerated heavy charged particles, mainly proton and carbon ions. Their salient features include an original dose-distribution, based on the Bragg curve, and in some of them an increased RBE at the range-end. Approximately 100 000 patients have been treated so far in approximately 40 centers worldwide. Outstanding outcomes have been substantiated in rare neoplasms using protons, such as ocular melanomas, skull base sarcomas, and pediatric malignancies, while only promising evidences have emerged using carbons. Assessing their place in more common tumor-sites, such as lung, pancreas, prostate, esophagus remains to be determined, and justifies the expansion of future particle therapy programs.

Uncertainties surround the radiobiological consequences of exposure to charged particles, despite the increasing use of accelerated ion beams for cancer treatment (hadrontherapy). In particular, little is known about the long-term effects on normal tissue at the beam entrance or in the distal part of the Spread-Out Bragg Peak (SOBP). Moreover, although the relative biological effectiveness (RBE) of particle radiation has been traditionally related to the radiation linear energy transfer (LET), it has become increasingly evident that radiation-induced cell death, as well as long term radiation effects, is not adequately described by this parameter. Hence, exploring the effectiveness of various ion beams at or around the Bragg peak of monoenergetic ion beams can prove useful to gain insights into the role played by parameters other than the particle LET in determining the outcome of particle radiation exposures. In this context, the upgrade of the Tandem irradiation facility at Naples University here described, has allowed us to perform a series of preliminary radiobiological measurements using proton and carbon ion beams. The facility is currently used to irradiate normal and cancer cell lines with ion beams such as oxygen and fluorine.