Abstract: Hadrontherapy with protons and carbon ions is a fast developing methodology in radiation oncology. The accelerators used and planned for this purpose are reviewed starting from the cyclotrons used in the thirties. As discussed in the first part of this paper, normal and superconducting cyclotrons are still employed, together with synchrotrons, for proton therapy while for carbon ion therapy synchrotrons have been till now the only option. The latest developments concern a superconducting cyclotron for carbon ion therapy, fast-cycling high frequency linacs and 'single room' proton therapy facilities. These issues are discussed in the second part of the paper by underlining the present challenges, in particular the treatment of moving organs.

Abstract: Background Approximately 50% of newly diagnosed cancer patients worldwide receive radiotherapy, most commonly with X-rays. Proton therapy has emerged as a promising alternative, offering complementary advantages over conventional X-rays due to its highly localized energy deposition at the Bragg peak, thereby reducing radiation exposure to surrounding healthy tissues. In recent years, advances in both technology and biomedicine have driven significant progress in proton therapy, with ongoing research aiming to minimize toxicity and long-term side effects while improving patients' quality of life. An emerging research direction investigates the combination of proton therapy with irradiated nanoparticles acting as radiosensitizers. This approach seeks synergistic effects that could further improve therapeutic outcomes. These effects arise from a complex interplay of physical, chemical, and biological mechanisms. Although previous in vitro and in vivo studies report promising radiosensitization effects of nanoparticles, the literature also includes contradictory results, and the underlying mechanisms remain under debate. This highlighting the need for systematic studies under well-controlled irradiation conditions of different nanoparticles and beam parameters, which are often difficult to perform due to the limited availability of particle accelerators and facilities suitably adapted for such experiments.Purpose This work investigates the radiosensitizing effect of gold nanoparticles under proton irradiation and optimizes the irradiation setup to enable more efficient and reproducible future experiments.Methods HeLa cells were used as the biological model for the radiobiological experiments. Irradiation conditions were optimized by incorporating a Mylar film into the culture plates to maintain a minimal medium volume and ensure rapid post-irradiation coverage. Cells with and without AuNPs were irradiated with 12.6 MeV proton beams. Radiosensitivity was assessed using clonogenic survival assays, and the radiosensitizing effect, together with its associated uncertainty, was quantified. DNA damage analysis was also performed to corroborate the observed effects and explore underlying mechanisms.Results The radiobiology experiments confirmed and quantified a significant radiosensitizing effect of gold nanoparticles (AuNPs) on HeLa cells at doses from 4 Gy, with Sensitization Enhancement Ratio (SER) values of 1.53 +/- 0.07 in 2022 and 1.30 +/- 0.20 in 2023 using 50 nm diameter AuNPs. Experiments in 2023 with 20 nm diameter AuNPs yielded a comparable SER of 1.38 +/- 0.18, indicating no significant size-dependent differences. The radiosensitizing effect exhibited dose-dependent amplification, with higher doses producing greater cell killing. Linear-Quadratic (LQ) model fits showed an increased alpha$\alpha$ parameter in the presence of AuNPs, consistent with an increase in non-repairable damage. This trend was further supported by double-strand break assays. Furthermore, oxidative stress assays showed that AuNPs do not increase basal ROS levels, but enhance ROS production under oxidative stress conditions.Conclusion The radiobiology experiments presented quantitatively confirm that both 20 and 50 nm diameter AuNPs enhance the radiosensitivity of HeLa cells under proton irradiation. The radiosensitizing effect increases with dose, indicating a dose-dependent response, while no significant differences were observed between nanoparticle sizes. Consistent trends of increased DNA double-strand breaks further support the observed radiosensitization. Evidence from oxidative stress assays suggests that AuNPs may enhance ROS production under oxidative conditions, potentially contributing to the observed radiosensitization and DNA damage.

Abstract: The radiation used in hadrontherapy treatments interacts with the patient body producing secondary particles, either neutral or charged, that can be used for dose and Bragg peak monitoring and to provide a fast feedback on the treatment plans. Recent results obtained from the authors on simplified setups (mono-energetic primary beams interacting with homogeneous tissue like target) have already indicated the correlation that exists between the flux of these secondaries coming from the target (e.g. protons and photons) and the position of the primary beam Bragg peak. In this paper, the measurements of charged particle fluxes produced by the interaction of a 220 MeV/u carbon ion beam at GSI, Darmstadt, with a polymethyl methacrylate target are reported. The emission region of protons (p), deuterons (d) and tritons (t) has been characterized using a drift chamber while the particle time-of-flight, used to compute the kinetic energy spectra, was measured with a LYSO scintillator.The energy released in the LYSO crystal was used for particle identification purposes. The measurements were repeated with the setup at 60 degrees and 90 degrees with respect to the primary beam direction. The accuracy on the fragments emission profile reconstruction and its relationship with the Bragg peak position have been studied. Based on the acquired experimental evidence, a method to monitor the dose profile and the position of the Bragg peak inside the target is proposed.