S. Lacombe

Platinum nanoparticles: a promising material for future cancer therapy?

Recently, the use of gold nanoparticles as potential tumor selective radiosensitizers has been proposed as a breakthrough in radiotherapy. Experiments in living cells and in vivo have demonstrated the efficiency of the metal nanoparticles when combined with low energy x-ray radiations (below conventional 1 MeV Linac radiation). Further studies on DNA have been performed in order to better understand the fundamental processes of sensitization and to further improve the method. In this work, we propose a new strategy based on the combination of platinum nanoparticles with irradiation by fast ions effectively used in hadron therapy. It is observed in particular that nanoparticles enhance strongly lethal damage in DNA, with an efficiency factor close to 2 for double strand breaks. In order to disentangle the effect of the nano-design architecture, a comparison with the effects of dispersed metal atoms at the same concentration has been performed. It is thus shown that the sensitization in nanoparticles is enhanced due to auto-amplified electronic cascades inside the nanoparticles, which reinforces the energy deposition in the close vicinity of the metal. Finally, the combination of fast ion radiation (hadron therapy) with platinum nanoparticles should strongly improve cancer therapy protocols.

Enhancement of radiation effect by heavy elements

The enhancement of radiobiological effects by heavy elements is reviewed. As an underlying mechanism, Auger effects have been stressed which can be induced via inner-shell photoabsorption or via excitation and/or ionization by secondary electrons. Latter channel of Auger induction expands the applicability of Auger enhancing phenomena to electron and hadron therapy. After discussion on the required characteristics for radiosensitizers, possibility of nanoparticles of Au or Pt is mentioned since they could be synthesized or modified as ideal radiosensitizers.

The use of theranostic gadolinium-based nanoprobes to improve radiotherapy efficacy

A new efficient type of gadolinium-based theranostic agent (AGuIX®) has recently been developed for MRI-guided radiotherapy (RT). These new particles consist of a polysiloxane network surrounded by a number of gadolinium chelates, usually 10. Owing to their small size (<5 nm), AGuIX typically exhibit biodistributions that are almost ideal for diagnostic and therapeutic purposes. For example, although a significant proportion of these particles accumulate in tumours, the remainder is rapidly eliminated by the renal route. In addition, in the absence of irradiation, the nanoparticles are well tolerated even at very high dose (10 times more than the dose used for mouse treatment). AGuIX particles have been proven to act as efficient radiosensitizers in a large variety of experimental in vitro scenarios, including different radioresistant cell lines, irradiation energies and radiation sources (sensitizing enhancement ratio ranging from 1.1 to 2.5). Pre-clinical studies have also demonstrated the impact of these particles on different heterotopic and orthotopic tumours, with both intratumoural or intravenous injection routes. A significant therapeutical effect has been observed in all contexts. Furthermore, MRI monitoring was proven to efficiently aid in determining a RT protocol and assessing tumour evolution following treatment. The usual theoretical models, based on energy attenuation and macroscopic dose enhancement, cannot account for all the results that have been obtained. Only theoretical models, which take into account the Auger electron cascades that occur between the different atoms constituting the particle and the related high radical concentrations in the vicinity of the particle, provide an explanation for the complex cell damage and death observed.

Mammalian cells loaded with platinum-containing molecules are sensitized to fast atomic ions

Purpose: This work investigates whether a synergy in cell death induction exists in combining atomic ions irradiation and addition of platinum salts. Such a synergy could be of interest in view of new cancer therapy protocol based on atomic ions – hadrontherapy – with the addition of radiosensitizing agents containing high-Z atoms. The experiment consists in irradiating by fast ions cultured cells previously exposed to dichloroterpyridine Platinum (PtTC) and analyzing cell survival by a colony-forming assay. Materials and methods: Chinese Hamster Ovary (CHO) cells were incubated for six hours in medium containing 350 μM PtTC, and then irradiated by fast ions C6+ and He2+, with Linear Energy Transfer (LET) within range 2–70 keV/μm. In some experiments, dimethyl sulfoxide (DMSO) was added to investigate the role of free radicals. The intracellular localization of platinum was determined by Nano Secondary Ion Mass Spectroscopy (Nano-SIMS). Results: For all LET examined, cell death rate is largely enhanced when irradiating in presence of PtTC. At fixed irradiation dose, cell death rate increases with increasing LET, while the platinum relative effect is larger at low LET. Conclusion: This finding suggests that hadrontherapy or protontherapy therapeutic index could be improved by combining irradiation procedure with concomitant chemotherapy protocols using platinum salts.

DNA strand breaks induced by low keV energy heavy ions

We present some results on the interaction of low energy atomic ions with DNA. Experiments consist of irradiation of dried DNA in vacuum with Ar ions at low keV energies for different time intervals. The DNA is placed back in solution and analysed by agarose gel electrophoresis. These experiments demonstrated the production of single and double strand breaks. The induction of these lesions could be due to several processes: direct collisions with DNA constituent atoms resulting in displacements, cascade recoil collisions of the constituent atoms, electron transfer processes between the ion and the DNA as well as breaks induced by molecular excitation and secondary electron interactions. Here we briefly discuss some aspects of direct and recoil collision processes.

Gadolinium-based nanoparticles to improve the hadrontherapy performances

UNLABELLED Nanomedicine is proposed as a novel strategy to improve the performance of radiotherapy. High-Z nanoparticles are known to enhance the effects of ionizing radiation. Recently, multimodal nanoparticles such as gadolinium-based nanoagents were proposed to amplify the effects of x-rays and g-rays and to improve MRI diagnosis. For tumors sited in sensitive tissues, childhood cases and radioresistant cancers, hadrontherapy is considered superior to x-rays and g-rays. Hadrontherapy, based on fast ion radiation, has the advantage of avoiding damage to the tissues behind the tumor; however, the damage caused in front of the tumor is its major limitation. Here, we demonstrate that multimodal gadolinium-based nanoparticles amplify cell death with fast ions used as radiation. Molecular scale experiments give insights into the mechanisms underlying the amplification of radiation effects. This proof-of-concept opens up novel perspectives for multimodal nanomedicine in hadrontherapy, ultimately reducing negative radiation effects in healthy tissues in front of the tumor. FROM THE CLINICAL EDITOR Gadolinium-chelating polysiloxane nanoparticles were previously reported to amplify the anti-tumor effects of x-rays and g-rays and to serve as MRI contrast agents. Fast ion radiation-based hadrontherapy avoids damage to the tissues behind the tumor, with a major limitation of tissue damage in front of the tumor. This study demonstrates a potential role for the above nanoagents in optimizing hadrontherapy with preventive effects in healthy tissue and amplified cell death in the tumor.

An apparatus for multiparametric studies of ion–surface collisions

This paper describes the design and tests of an ultrahigh vacuum apparatus built for the study of particle surface interactions, with emphasis on ion scattering experiments. The system was designed to provide facilities for angle resolved electron spectroscopy, ion scattering spectroscopy (ISS), Auger electron spectroscopy (AES), and ultraviolet photoelectron spectroscopy (UPS). It has provisions for photon spectroscopy and fixed angle time‐of‐flight (TOF) scattering and recoiling spectrometry. Mass selected ion beams in the energy range from a few eV to a few keV can be produced in a continuous or pulsed mode. Two independent, parallel plate tandem electrostatic analyzers, which can rotate around the sample are employed. The angular range spanned is analysis‐type dependent and varies from 0° to 135°. One of the analyzers was designed for low energy secondary electron spectroscopy (0–100 eV) and the other one for ISS and AES measurements in the energy range from a few eV to 5 keV. The system disposes of a...

Cell localisation of gadolinium-based nanoparticles and related radiosensitising efficacy in glioblastoma cells

Recently, the addition of nanoparticles (NPs) has been proposed as a new strategy to enhance the effect of radiotherapy particularly in the treatment of aggressive tumors such as glioblastoma. The physical processes involved in radiosensitisation by nanoparticles have been well studied although further understanding of its biological impact is still lacking, and this includes the localisation of these NPs in the target cells. Most studies were performed with NPs tagged with fluorescent markers. However, the presence of these markers can influence the NPs uptake and localisation. In this study, a set of methods was used to unambiguously and fully characterise the uptake of label-free NPs, their co-localisation with cell organelles, and their radiosensitising efficacy. This set was applied to the case of gadolinium-based nanoparticles (GdBN) used to amplify the radiation killing of U87 glioblastoma cells extracted from highly aggressive human tumor. For the first time, Synchrotron Radiation Deep UV (SR-DUV) microscopy is proposed as a new tool to track label-free GdBN. It confirmed the localisation of the NPs in the cytoplasm of U87 cells and the absence of NPs in the nucleus. In a second step, Transmission Electron Microscopy (TEM) demonstrated that GdBN penetrate cells by endocytosis. Third, using confocal microscopy it was found that GdBN co-localise with lysosomes but not with mitochondria. Finally, clonogenic assay measurements proved that the presence of NPs in the lysosomes induces a neat amplification of the killing of glioblastoma cells irradiated by gamma rays. The set of combined experimental protocols—TEM, SR-DUV and confocal microscopy—demonstrates a new standard method to study the localisation of label-free NPs together with their radiosensitising properties. This will further the understanding of NP-induced radiosentisation and contribute to the development of nanoagents for radiotherapy.

Dynamics of excited state production in the scattering of inert gas atoms and ions from Mg and Al surfaces

Abstract We present results of a detailed study of the production of electronically excited states in the scattering of ionic or neutral inert gas projectiles in the keV energy range at Al and Mg surfaces. The complementary observation of scattered particles (neutrals or ions), secondary electrons and photons leads to a rather complete description of the successive stages of inelastic scattering events. Efficient neutralisation of the incident ions occurs, when they approach the surface. This is clearly demonstrated by the strong similarities between results obtained for incoming ions and incoming ground-state neutrals. The characteristics of the scattered particle distributions, the observation of scattered ions, and also of some excited states by electron and photon spectroscopy, delineates the decisive importance of short-distance binary collisions with atoms of the surface, in the production of these species. A detailed comparison with the “inverse” collisional systems in the gas phase shows that the same kind of primary excitations as described in the quasi-molecular orbital promotion model are operative and allows, for example, predictions about which of projectile and/or target atoms can be excited. Some very strong differences to gas-phase collisions are also demonstrated. They stress the importance of surface-specific effects, such as the role of resonant or Auger electron transfers between the metal surface and the receding particle in defining the final state population. In particular, an interesting surface-induced core rearrangement effect is emphasised, and different rearrangement mechanisms are presented and discussed.

Irradiation of DNA loaded with platinum containing molecules by fast atomic ions C6+ and Fe26+

Purpose: In order to study the role of the Linear Energy Transfer (LET) of fast atomic ions in platinum-DNA complexes inducing breaks, DNA Plasmids were irradiated by C6+ and Fe26+ ions. Material and methods: DNA Plasmids (pBR322) loaded with different amounts of platinum contained in a terpyridine-platinum molecule (PtTC) were irradiated by C6+ ions and Fe26+ ions. The LET values ranged between 13.4 keV/μm and 550 keV/μm. In some experiments, dimethyl sulfoxide (DMSO) was added. Results: In all experiments, a significant increase in DNA strand breaks was observed when platinum was present. The yield of breaks induced per Gray decreased when the LET increased. The yield of single and double strand breaks per plasmid per track increased with the LET, indicating that the number of DNA breaks per Gray was related to the number of tracks through the medium. Conclusions: These findings show that more DNA breaks are induced by atomic ions when platinum is present. This effect increases for low LET heavy atoms. As DSB induction may induce cell death, these results could open new perspectives with the association of hadrontherapy and chemotherapy. Thus the therapeutic index might be improved by loading the tumour with platinum salts.