No abstract

DNA damage and repair studies are at the core of the radiation biology field and represent also the fundamental principles informing radiation therapy (RT). DNA damage levels are a function of radiation dose, whereas the type of damage and biological effects such as DNA damage complexity, depend on radiation quality that is linear energy transfer (LET). Both levels and types of DNA damage determine cell fate, which can include necrosis, apoptosis, senescence or autophagy. Herein, we present an overview of current RT modalities in the light of DNA damage and repair with emphasis on medium to high-LET radiation. Proton radiation is discussed along with its new adaptation of FLASH RT. RT based on α-particles includes brachytherapy and nuclear-RT, that is proton-boron capture therapy (PBCT) and boron-neutron capture therapy (BNCT). We also discuss carbon ion therapy along with combinatorial immune-based therapies and high-LET RT. For each RT modality, we summarise relevant DNA damage studies. Finally, we provide an update of the role of DNA repair in high-LET RT and we explore the biological responses triggered by differential LET and dose.

Many different tumor-targeted strategies are under development worldwide to limit the side effects and improve the effectiveness of cancer therapies. One promising method is to enhance the radiosensitization of the cancer cells while reducing or maintaining the normal tissue complication probability during radiation therapy using metallic nanoparticles (NPs). Radiotherapy with MV photons is more commonly available and applied in cancer clinics than high LET particle radiotherapy, so the addition of high-Z NPs has the potential to further increase the efficacy of photon radiotherapy in terms of NP radiosensitization. Generally, when using X-rays, mainly the inner electron shells are ionized, which creates cascades of both low and high energy Auger electrons. When using high LET particles, mainly the outer shells are ionized, which give electrons with lower energies than when using X-rays. The amount of the produced low energy electrons is higher when exposing NPs to heavy charged particles than when exposing them to X-rays. Since ions traverse the material along tracks, and therefore give rise to a much more inhomogeneous dose distributions than X-rays, there might be a need to introduce a higher number of NPs when using ions compared to when using X-rays to create enough primary and secondary electrons to get the desired dose escalations. This raises the questions of toxicity. This paper provides a review of the fundamental processes controlling the outcome of metallic NP-boosted photon beam and ion beam radiation therapy and presents some experimental procedures to study the biological effects of NPs’ radiosensitization. The overview shows the need for more systematic studies of the behavior of NPs when exposed to different kinds of ionizing radiation before applying metallic-based NPs in clinical practice to improve the effect of IR therapy.

The combined effects of ionizing radiation (IR) with high-z metallic nanoparticles (NPs) such as gold has developed a growing interest over the recent years. It is currently accepted that radiosensitization is not only attributed to physical effects but also to underlying chemical and biological mechanisms’ contributions. Low- and high-linear energy transfer (LET) IRs produce DNA damage of different structural types. The combination of IR with gold nanoparticles may increase the clustering of energy deposition events in the vicinity of the NPs due to the production mainly of photoelectrons and Auger electrons. Biological lesions of such origin for example on DNA are more difficult to be repaired compared to isolated lesions and can augment IR’s detrimental effects as shown by numerous studies. Transmission electron microscopy (TEM) offers a unique opportunity to study the complexity of these effects on a very detailed cellular level, in terms of structure, including nanoparticle uptake and damage. Cellular uptake and nanoparticle distribution inside the cell are crucial in order to contribute to an optimal dose enhancement effect. TEM is mostly used to observe the cellular localization of nanoparticles. However, it can also provide valuable insights on the NPs’ radiosensitization pathways, by studying the biochemical mechanisms through immunogold-labelling of antigenic sites at ultrastructural level under high resolution and magnification. Here, our goal is to describe the possibilities, methodologies and proper use of TEM in the interest of studying NPs-based radiosensitization mechanisms.