To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1nu/nu mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research.

The thesis at hand addresses design, characterization and experimental testing of pulsed high-field magnets for utilization in the field of laser-plasma physics. The central task was to establish a technology platform that allows to manipulate laser-driven ion sources in a way that the accelerated ions can be used in complex application studies, e.g. radiobiological cell or tumor irradiation. Laser-driven ion acceleration in the regime of target normal sheath acceleration (TNSA) offers the unique opportunity to accelerate particles to kinetic energies of few 10MeV on the micrometer scale. The generated bunches are short, intense, show broad exponentially decaying energy spectra and high divergence. In order to efficiently use the generated particles, it is crucial to gain control over their divergence directly after their production. For most applications it additionally is favorable to reduce the energy spread of the beam. This work shows that the developed pulsed high-field magnets, so-called solenoids (cylindrical magnets), can efficiently capture, transport and focus laser-accelerated protons. The chromaticity of the magnetic lens thereby provides for energy selection. Three prototype solenoids, adapted to fit different application scenarios, and associated current pulse drivers have been developed. The magnets generate fields of several 10 T. Pulse durations are of the order of one millisecond and thus the fields can be considered as quasi-static for laser-plasma interaction processes taking place on the ps- to ns-scale. Their high field strength in combination with abandoning magnetic cores make the solenoids compact and light-weight. The presented experiments focus on a solenoid magnet designed for the capture of divergent laser-driven ion beams. They have been carried out at the 6MV tandetron accelerator and the laser acceleration source Draco of Helmholtz-Zentrum Dresden – Rossendorf as well as at the PHELIX laser of GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt.

To optimize neoadjuvant radiochemotherapy of pancreatic ductal adenocarcinoma (PDAC), the value of new irradiation modalities such as proton therapy needs to be investigated in relevant preclinical models. We studied individual treatment responses to RCT using patient-derived PDAC organoids (PDO). Four PDO lines were treated with gemcitabine, 5-fluorouracile (5FU), photon and proton irradiation and combined RCT. Therapy response was subsequently measured via viability assays. In addition, treatment-naive PDOs were characterized via whole exome sequencing and tumorigenicity was investigated in NMRI Foxn1nu/nu mice. We found a mutational pattern containing common mutations associated with PDAC within the PDOs. Although we could unravel potential complications of the viability assay for PDOs in radiobiology, distinct synergistic effects of gemcitabine and 5FU with proton irradiation were observed in two PDO lines that may lead to further mechanistical studies. We could demonstrate that PDOs are a powerful tool for translational proton radiation research.