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Institute
In Germany more than 200.000 persons die of cancer every year, which makes it the second most common cause of death. Chemotherapy and radiation therapy are often combined to exploit a supra-additive effect, as some chemotherapeutic agents like halogenated nucleobases sensitize the cancerous tissue to radiation. The radiosensitizing action of certain therapeutic agents can be at least partly assigned to their interaction with secondary low energy electrons (LEEs) that are generated along the track of the ionizing radiation. In the therapy of cancer DNA is an important target, as severe DNA damage like double strand breaks induce the cell death. As there is only a limited number of radiosensitizing agents in clinical practice, which are often strongly cytotoxic, it would be beneficial to get a deeper understanding of the interaction of less toxic potential radiosensitizers with secondary reactive species like LEEs. Beyond that LEEs can be generated by laser illuminated nanoparticles that are applied in photothermal therapy (PTT) of cancer, which is an attempt to treat cancer by an increase of temperature in the cells. However, the application of halogenated nucleobases in PTT has not been taken into account so far. In this thesis the interaction of the potential radiosensitizer 8-bromoadenine (8BrA) with LEEs was studied. In a first step the dissociative electron attachment (DEA) in the gas phase was studied in a crossed electron-molecular beam setup. The main fragmentation pathway was revealed as the cleavage of the C-Br bond. The formation of a stable parent anion was observed for electron energies around 0 eV. Furthermore, DNA origami nanostructures were used as platformed to determine electron induced strand break cross sections of 8BrA sensitized oligonucleotides and the corresponding nonsensitized sequence as a function of the electron energy. In this way the influence of the DEA resonances observed for the free molecules on the DNA strand breaks was examined. As the surrounding medium influences the DEA, pulsed laser illuminated gold nanoparticles (AuNPs) were used as a nanoscale electron source in an aqueous environment. The dissociation of brominated and native nucleobases was tracked with UV-Vis absorption spectroscopy and the generated fragments were identified with surface enhanced Raman scattering (SERS). Beside the electron induced damage, nucleobase analogues are decomposed in the vicinity of the laser illuminatednanoparticles due to the high temperatures. In order to get a deeper understanding of the different dissociation mechanisms, the thermal decomposition of the nucleobases in these systems was studied and the influence of the adsorption kinetics of the molecules was elucidated. In addition to the pulsed laser experiments, a dissociative electron transfer from plasmonically generated ”hot electrons” to 8BrA was observed under low energy continuous wave laser illumination and tracked with SERS. The reaction was studied on AgNPs and AuNPs as a function of the laser intensity and wavelength. On dried samples the dissociation of the molecule was described by fractal like kinetics. In solution, the dissociative electron transfer was observed as well. It turned out that the timescale of the reaction rates were slightly below typical integration times of Raman spectra. In consequence such reactions need to be taken into account in the interpretation of SERS spectra of electrophilic molecules. The findings in this thesis help to understand the interaction of brominated nucleobases with plasmonically generated electrons and free electrons. This might help to evaluate the potential radiosensitizing action of such molecules in cancer radiation therapy and PTT.
The excitation of localized surface plasmons in noble metal nanoparticles (NPs) results in different nanoscale effects such as electric field enhancement, the generation of hot electrons and a temperature increase close to the NP surface. These effects are typically exploited in diverse fields such as surface-enhanced Raman scattering (SERS), NP catalysis and photothermal therapy (PTT). Halogenated nucleobases are applied as radiosensitizers in conventional radiation cancer therapy due to their high reactivity towards secondary electrons. Here, we use SERS to study the transformation of 8-bromoadenine (8BrA) into adenine on the surface of Au and AgNPs upon irradiation with a low-power continuous wave laser at 532, 633 and 785 nm, respectively. The dissociation of 8BrA is ascribed to a hot-electron transfer reaction and the underlying kinetics are carefully explored. The reaction proceeds within seconds or even milliseconds. Similar dissociation reactions might also occur with other electrophilic molecules, which must be considered in the interpretation of respective SERS spectra. Furthermore, we suggest that hot-electron transfer induced dissociation of radiosensitizers such as 8BrA can be applied in the future in PTT to enhance the damage of tumor tissue upon irradiation.