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Thomas Schlathölter,1 Pierre Eustache,2 Erika Porcel,2 Daniela Salado,2 Lenka Stefancikova,2 Olivier Tillement,3 Francois Lux,3 Pierre Mowat,3 Aleksandra K Biegun,4 Marc-Jan van Goethem,4 Hynd Remita,5 Sandrine Lacombe2 1Zernike Institute for Advanced Materials, University of Groningen, Groningen, the Netherlands; 2Institut des Sciences Moléculaires d’Orsay (ISMO), Univ. Paris Sud, CNRS, Université Paris Saclay, Orsay Cedex, 3Institut Lumière Matière, Villeurbanne Cedex, France; 4Kernfysisch Versneller Instituut – Center for Advanced Radiation Technology (KVI-CART), University of Groningen, Groningen, the Netherlands; 5Laboratoire de Chimie Physique, Universite Paris-Sud, Orsay Cedex, France Abstract: 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/µm) 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 (>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. Keywords: gadolinium-based nanoparticles, platinum nanoparticles, nanosensitization, theranostics

Background: In 1984 PSI started the ocular proton therapy program called OPTIS. To date more than 5200 eye tumours have been treated using a 72 MeV Philips cyclotron. Cyclotron reliability and maintenance issues led to the start of the PROSCAN project in 2000, resulting in the 250 MeV COMET cyclotron[for full text, please go to the a.m. URL], PTCOG 48; Meeting of the Particle Therapy Co-Operative Group

We present in this paper transverse momentum and rapidity distributions of pi(0)-mesons measured in Ar-36+ Au-197 collisions at 25A and 35A MeV beam energies with the TAPS spectrometer at the KVI AGOR accelerator. p(t) spectra are consistent with thermal-like emission of pi(0)-mesons with temperature parameters considerably lower than other available data at the same beam energies. Rapidity distributions point to the contribution of two different pi(0) production mechanisms.

Photon angular distributions and energy spectra up to the kinematic limit have been measured in 190 MeV proton reactions with light and heavy targets. For the first time photon spectra in dependence of scattered protons have been measured to investigate the influence of the multiple-scattering process on the photon production. Based on predictions for the free pn bremsstrahlung amplitude a strong suppression of bremsstrahlung relative to a quasi-free production model is observed in the low-energy regime of the photon spectrum in p+nucleus reactions. We attribute this effect partly to modifications of the bremsstrahlung amplitude in the nuclear medium and partly to interference of proton amplitudes due to multiple scattering of nucleons.

Exclusive differential cross sections of virtual-photon radiative proton capture in pd --> He-3 + e(+)e(-) at a proton energy of 190 MeV have been measured for the first time. The leptonic-angle dependence of the measured cross section is exploited in order to determine the electromagnetic response functions in the time-like region. The data are compared to a relativistic gauge-invariant impulse approximation and a Faddeev calculation. Differences between theoretical predictions and data are discussed in terms of enhanced magnetic radiation possibly originating from virtual Delta excitations.

Photon angular distributions and energy spectra up to the kinematical limit have been measured in proton reactions with light and heavy targets. For the first time the dependence of photon spectra on scattered protons has been measured to investigate the influence of multiple-scattering processes on the photon production. A strong suppression of bremsstrahlung relative to a quasi-free production model using the free pn bremsstrahlung cross section is observed in the low-energy regime of the photon spectrum in p + nucleus reactions. We attribute this effect to modifications of the bremsstrahlung amplitude in the nuclear medium and to interference of photon amplitudes due to multiple scattering of nucleons.

Virtual bremsstrahlung yields measured in (p) over bar+p-->p+p+e(+)+e(-) and (p) over bar+d-->He-3+e(+)+e(-) are presented. The experiments were performed with a 190 MeV polarized proton beam obtained from the cyclotron AGOR at KVI in Groningen. Differential cross sections, response functions and analyzing powers were obtained for both reactions in exclusive measurements in which all outgoing particles were measured in a coincidence setup between SALAD and TAPS. The data are compared with gauge-invariant calculations using a NN T-matrix fitted to elastic phase-shifts. For pp-->ppe(+) e(-) a reasonable agreement is found for all measured virtual-photon invariant masses, M-gamma > 15 MeV/c(2) up to 80 MeV/c(2). For the pd-->He-3 e(+)e(-) angular distributions, the calculations underestimate the data for theta(CM) >100 degrees similar to what is found in the real-photon capture reaction.

A series of bremsstrahlung measurements have been performed at KVI with the 190 MeV polarized proton beam of the new superconducting cyclotron, AGOR. The aim of these measurements is to investigate the dynamics of interactions involving intermediate off-shell nucleons. Nucleon-nucleon bremsstrahlung is the most fundamental process used for such studies as it involves the strong interaction between two nucleons and the well-known electromagnetic interaction. The present experiment provides the most accurate experiment to date on the proton-proton system. The accuracy is high enough to investigate higher order effects such as the virtual Delta-isobar and meson exchange currents. Surprisingly, none of the microscopic calculations is able to describe the data both in magnitude and in shape.

For the first time an exclusive proton-deuteron bremsstrahlung experiment has been performed in which all the exit channels can be identified separately. Preliminary results indicate we are able to identify the different exit channels with high accuracy. For the 3 and 4-body final state, no high quality calculations are available at the present time.

A beam-polarimeter for medium energy protons and deuterons (E=100-200 MeV) has been constructed. Its operation is based on the p + d, p + p and d + p elastic scattering with coincident detection of both particles in 4 independent planes. The 16 detectors of the polarimeter have a phoswich construction to ensure particle identification. With this device the analyzing power, A(y), of p + p elastic scattering has been measured at 190 MeV for CM-angles of 25 degrees to 115 degrees in two planes, monitored by p Sp elastic scattering in the two other planes. The target was mixed CH2/CD2. This allowed for simultaneous extraction of A(y)(p, d) and the beam polarizations. The analyzing power is compared with calculations based on the Bonn-potential including partial waves up to J = 5.

Photon energy spectra up to the kinematic limit have been measured in 190 MeV proton reactions with light and heavy nuclei to investigate the influence of the multiple-scattering process on the photon production. Relative to the predictions of models based on a quasi-free production mechanism a strong suppression of bremsstrahlung is observed in the low-energy region of the photon spectrum. We attribute this effect to the interference of photon amplitudes due to multiple scattering of nucleons in the nuclear medium., Comment: 12 pages, 3 figures, submitted to Phys. Rev. Lett