# Co-Adjuvant Nanoparticles for Radiotherapy Treatments of Oncological Diseases
## 2 Radiotherapy Mechanism  
Radiotherapy is one of the most effective and widely used cancer therapeutic modalities. About 50% of cancer patients are treated with radiotherapy for curative and palliative purposes both as single therapeutic modality and in combination with other treatment methods [66; 67]. Although RT cannot be applied to all types of cancer, it is established as a principal option for treatment of many malignancies, such as breast carcinoma, lung carcinoma, melanoma, gastrointestinal cancers, head and neck cancers, gynecological cancers, hematologic malignancies, prostate or cervix tumors, central nervous system neoplasms and thyroid carcinomas, as well as for an effective reduction of pain in the of case bone and brain metastases [68; 69]. RT exploits ionizing beams--X-rays or radiation emitted by radionuclides--to stop the rapid proliferation of cancer cells and to achieve the therapeutic goals [70; 71]. For the description of the RT mechanism, this review focuses mainly on RT applied by an external X-ray source. As summarized in Figure 1, the interaction of the high energy radiation within tissues induces the killing of tumor cells directly by the damage of the DNA and of the molecular structure leading to the termination of cell division and proliferation,and even to cell necrosis or apoptosis; otherwise, cancer cells destruction can arise indirectly from the formation of cytotoxic ROS upon interaction with the cellular aqueous environment [72; 73]. A detailed description of biochemical reactions occurring in cellular environment upon the interaction with the ionizing radiation is depicted by [PERSON] and co-worker in Ref. [65]. Briefly, in cellular environment, water radiolysis by ionizing radiation results in the formation of several species, mainly: \(e-aq\) (hydrated electrons), HO\(\bullet\) (hydroxyl radicals), H\(\bullet\) (hydrogen radicals), H\({}_{2}\) (radiolytic hydrogen), H\({}_{2}\)O\({}_{2}\) (hydrogen peroxide), and HO\({}^{\bullet}\)2 (hydroperoxyl radical). Afterwards, these products can react and create further ROS, such as O\({}^{-}\)2 (superoxide), organic radicals (R\(\bullet\)), hydroperoxides (ROOH), and singlet oxygen (\({}^{1}\)O\({}_{2}\)). Under physiological conditions cells generate a certain amount of ROS, whose concentration is regulated by the antioxidant system to maintain cellular homeostasis. Perturbing the cellular balance by radiation-induced ROS creation leads to oxidative stress that can trigger DNA damage and other cell death mechanisms, for instance by necrosis, apoptosis, autophagy, mutation, and senescence. Whatever the cancer cells killing mechanism, i.e., by physically direct ionization or using free radicals by water ionization, the goal of radiotherapy is to deliver the maximum dose to the target tumor tissue while safeguarding the surrounding normal tissue. Clinical radiotherapy uses high-energy external X-ray beam, from 6 MeV up to about 20 MeV, from linear accelerators. In typical launched protocols, patients are treated through fractionated regime with dose of 1.8-2 Gy over the course of 4-8 weeks to limit toxicity to normal tissues [74] but in advanced treatment planning the delivered dose to cancer can reach values close to 15-20 Gy [75]. Interactions of such X-rays with biological tissue can occur by (1) photoelectric effect, (2) Compton effect, and (3) pair production, according to the energy of the external X-ray source. In clinical RT the X-rays beams of few tens of MV are widely used for deep seated tumors, while low energy beams (up to 200 kV) have very few applications due to the lower penetration depth (<5 mm) [76]; at these working energies the Compton and the photoelectric effects are dominant (Figure 2), and the deposit of  
Figure 1: The direct and indirect cellular effects of ionizing radiation on macromolecules.