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.

The contemporary lifestyle of the last decade has undeniably caused a tremendous increase in oxidative-stress-inducing environmental sources. This phenomenon is not only connected with the rise of ROS levels in multiple tissues but is also associated with the induction of senescence in different cell types. Several signaling pathways that are associated with the reduction in ROS levels and the regulation of the cell cycle are being activated, so that the organism can battle deleterious effects. Within this context, autophagy plays a significant role. Through autophagy, cells can maintain their homeostasis, as if it were a self-degradation process, which removes the “wounded” molecules from the cells and uses their materials as a substrate for the creation of new useful cell particles. However, the role of autophagy in senescence has both a “dark” and a “bright” side. This review is an attempt to reveal the mechanistic aspects of this dual role. Nanomedicine can play a significant role, providing materials that are able to act by either preventing ROS generation or controllably inducing it, thus functioning as potential therapeutic agents regulating the activation or inhibition of autophagy.

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.

Purpose: Numerous studies focus on cancer therapy worldwide, and although many advances have been recorded, the complexity of the disease dictates thinking out of the box to confront it. This study reviews some of the currently available ionizing (IR) and non-ionizing radiation (NIR)-based treatment methods and explores their possible combinations that lead to synergistic, multimodal approaches with promising therapeutic outcomes. Conclusion: Traditional techniques, like radiotherapy (RT) show decent results, although they cannot spare 100% the healthy tissues neighboring with the cancer ones. Targeted therapies, such as proton and photodynamic therapy (PT and PDT, respectively) present adequate outcomes, even though each one has its own drawbacks. In order to overcome these limitations, the combination of therapeutic modalities has been proposed and has already been showing promising results. At the same time, the recent advances in nanotechnology in the form of nanoparticles enhance cancer therapy, making multimodal treatments worthy of exploring and studying. The combination of RT and PDT has reached the level of clinical trials and is showing promising results. Moreover, in vitro and in vivo studies of nanoparticles with PDT have also provided beneficial results concerning enhanced radiation treatments. In any case, novel and multimodal approaches have to be adopted in order to achieve personalized, enhanced and effective cancer treatment.

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.

Hyperthermia acts as a powerful adjuvant to radiation therapy and chemotherapy. Recent advances show that gold nanoparticles (Au-NPs) can mediate highly localized thermal effects upon interaction with laser radiation. The purpose of the present study was to investigate via in silico simulations the mechanisms of Au-NPs and microwave-induced hyperthermia, in correlation to predictions of tumor control (biological endpoints: tumor shrinkage and cell death) after hyperthermia treatment. We also study in detail the dependence of the size, shape and structure of the gold nanoparticles on their absorption efficiency, and provide general guidelines on how one could modify the absorption spectrum of the nanoparticles in order to meet the needs of specific applications. We calculated the hyperthermia effect using two types of Au-NPs and two types of spherical tumors (prostate and melanoma) with a radius of 3 mm. The plasmon peak for the 30 nm Si-core Au-coated NPs and the 20 nm Au-NPs was found at 590 nm and 540 nm, respectively. Considering the plasmon peaks and the distribution of NPs in the tumor tissue, the induced thermal profile was estimated for different intervals of time. Predictions of hyperthermic cell death were performed by adopting a three-state mathematical model, where “three-state” includes (i) alive, (ii) vulnerable, and (iii) dead states of the cell, and it was coupled with a tumor growth model. Our proposed methodology and preliminary results could be considered as a proof-of-principle for the significance of simulating accurately the hyperthermia-based tumor control involving the immune system. We also propose a method for the optimization of treatment by overcoming thermoresistance by biological means and specifically through the targeting of the heat shock protein 90 (HSP90), which plays a critical role in the thermotolerance of cells and tissues.