# Co-Adjuvant Nanoparticles for Radiotherapy Treatments of Oncological Diseases
## 3 Nanoparticles in Radiotherapy
### Passive Nanoparticles as Enhancers of Energy Deposition in RT  
The scientific and medical communities strive to find X-ray based therapeutic solutions with the aim to improve the survival rate and life quality in oncological patients subjected to RT by reducing the illness recurrence, which is related mostly to the massive doses required for stopping the cancer cells division but delivered also towards the surrounding healthy tissue. High Z and dense inorganic nanomaterials represent the key to reduce RT parameters, such as external beam energy, delivered dose, and exposition time, while boosting all the toxic and fatal effects of the radiation [74,76]. The idea to exploit high Z materials comes from simple considerations. Indeed, the presence of heavy NPs in a regime of low energy ionizing radiation (<60 keV) maximizes the X-ray beams attenuation by photoelectric effects, whose cross section \(\sigma\) depends on (Z/E) n, with \(n\cong\) 3-4 [77]. This dependency reveals that high Z materials turn out to be supportive in RT by enhancing the deposit of energy in the tumor and in the proximity of the malignant cells (thus, the dose delivered during radiotherapy) [81]. Since the early 1970s, the ability of diverse materials, like water/tissue equivalent materials, alloys of metals, and heavy metals, at stopping the ionizing radiation have been tested for applications in radiotherapy [82]. Later, it has been discovered that metal implants, composed by aluminum, tin, stainless steel, titanium, and lead, can alter the delivered doses in radiotherapy in patients affected by neck and mandibular cancers, due to the difference in Z value between the biological tissues and the metals [83,84]. In the last few decades, the scientific research has looked at the capacity of nanosized heavy metal particles in promoting the dose delivery in cancer tissue as a chance to improve the RT procedure and its therapeutic outcomes, due to the correlation between the enhanced energy dose and the increased cancer cell destruction [85]. Over the past few years, NP sensitizers have been proposed in combination with radiotherapy in order to improve tumor response and control the disease growth. For instance, there has been lot of interest in metallic--gold, gadolinium, silver, bismuth, and platinum--and bimetallic based NPs, as well as in nanometric metal oxides [86,87]. Thanks to the high atomic number, good biocompatibility, and relatively strong photoelectric absorption coefficient, gold nanoparticles (AuNPs, \(Z=79\)) are largely studied for diagnostic and therapeutic applications in cancer therapy [88]. Especially, Au nanoparticles have been under investigation as possible agents for amplification of radiation dose in tumors, in the so called \"gold nanoparticle-assisted radiation therapy\". From the first decades of 2000's, AuNPs' action has been predicted to increase the fraction of the X-rays energy deposited close to gold NPs because of increased photoelectric interactions, thereby enhancing the local radiation dose also according to their shape, functionalization, concentration, and intracellular distribution [89]. In vivo studies performed by [PERSON] et al. [90] and [PERSON] et al. [91] by injecting Au NPs and microspheres in tumor-bearing mice, have reported the occurrence of biologically effective dose enhancement by using kilovoltage photon beams; while the use of isotopes producing low-energy photons has been foreseen for significantly improving the clinical potential of interstitial brachytherapy. More recent works assess the Au actions considering the increment of dose together with the corollary activation of ROS within malignant cells [92] (see for example Figure 3 reproduced from Ref. [92]). Ongoing research promotes the optimization of nanoparticles targeting and functionalizationto reduce the total doses to be delivered, and to combine ionizing radiation with other therapeutic modalities [93; 94; 95; 96]  
A valid candidate as sensitizers of RT is Gadolinium (Gd, Z = 64).