Electron attachment to radiosensitizer molecules

Collisions between electrons and molecules initiate and drive many important chemical reactions associated with radiation physics and chemistry, environmental physics and chemistry and technical applications. Moreover, life sciences are a rapidly growing area where the important role of electron driven reactions is only now beginning to be recognized. In radiation therapy different so-called radiosensitizers have been suggested which should increase the sensitivity of tumors towards ionizing radiation. Those sensitizers are particularly promising for hypoxic tumors, which possess a lack of oxygen. Once accumulated in tumor cells, radiosensitizers become activated by attachment of an electron, i.e. anions of the radiosensitizer are formed. Electrons are abundantly generated during the irradiation of cell tissue in radiation therapy. The further action leading to the increase of sensitivity is not clarified yet. One hypothesis suggests that the anion formed may bind itself to damaged sites of the DNA and makes this damage permanently. An alternative model suggests rapid decomposition of the anion which leads to the release of damaging neutral radicals like OH or NO, which attack the DNA. In the present project we will investigate electron attachment to various potential radiosensitiser molecules and identify reaction pathways after anion formation. We will study a broad variety of molecules, clinically applied molecules as well as molecules suggested here for the first time and may find an application in radiation therapy in the future. In order to follow electron induced reactions, we will focus on the molecular level, i.e., molecules will be studied in the gas phase or surrounded by few neighboring molecules. Such systems allow the utilization of mass spectrometry, where the unambiguous identification of reaction products is possible. We will be particularly interested in the question, if the radiosensitizer will be indeed stable upon the electron capture, or if the decay into a fragment anion and a neutral radical occurs. The used experimental method allows the choice of the neighboring molecules of the radiosensitizer. We will study the effect of neighborhood by several water molecules. In addition, we will add oxygen molecules, in order to investigate a proposed deactivation mechanism of radiosensitizers by oxygen. In this case an electron transfer of the radiosensitizer anion to molecular oxygen should occur before the decomposition starts. This process was proposed to be the active mechanism in non- hypoxic cells and we will study its efficiency for different radiosensitizers.

Highly-energetic radiation like x-rays or other ionizing radiation may damage biological tissue. This effect is known since long time and is exploited for the treatment of tumors in radiation therapy. A significant problem in radiation therapy is the limited efficiency of radiation in tumor tissue, since these regions are often hypoxic. A certain class of molecules, so-called radiosensitizers, should compensate this limiting effect of low oxygen concentrations and induce additional tumor damage in the interaction with radiation. In this project, different radiosensitizers were irradiated by low-energy electrons. Such electrons are released, when ionizing radiation interacts with biological matter. One essential question in this context is related to possible binding of low-energy electrons with radiosensitizers. In this case, anions are formed which may subsequently lead to damage of tumor tissue. The present project results indicate that low-energy electrons can very efficiently form anions from radiosensitizers. The results extend the common hypothesis in radiation biology that radiosensitizers become negatively charged by the interaction with enzymes. The investigated nimorazole radiosensitizer turned out to be a particularly efficient electron scavenger. This molecule received high attention regarding the possible application of radiosensitizers, since it passed all clinical trials and is used in Denmark for the treatment of certain head and neck cancers. Our project results for nimorazole support the hypothesis about the activation of the molecule in tumor tissue upon anion formation. We additionally investigated also other molecules with the similar basic structure like nimorazole. These molecules failed in clinical trials due to large side effects. Concerning initial anion formation, they however showed similar properties regarding initial anion formation like nimorazole. Thus, the required lower dose of these radiosensitizers is not compensable by an increased electron attachment efficiency. We also studied other classes of radiosensitizers, which should show different mechanisms of action in cells. Indeed, for these compounds we also observed different electron attachment properties. This result supports the suggestion, that secondary electrons released by ionizing radiation play a role in the activation of radiosensitizers. Thus, the present project results enhance the knowledge about the fundamental molecular properties of radiosensitizers. In the future, this knowledge may be used for the design of new radiosensitizers, in order to improve the effects of radiation therapy.