# Co-Adjuvant Nanoparticles for Radiotherapy Treatments of Oncological Diseases
## 4 The Effect of the Energy Release vs. X-PDT Efficacy  
The perspective of discovering novel materials mostly shaped in form of organic and inorganic nanoparticle or hybrids demands a deeper comprehension of the processes occurring within the material after the interaction with the ionizing radiation. Indeed, the reduced material dimension is critical in presence of high energy ionizing radiation, as the migration distance of secondary charges generated in the NPs along the track from the point of the ionizing event (relaxation mechanisms) are significantly larger than the common nanometric radius of the NPs. Therefore, a fraction of energy escapes from the NPs, limiting the efficiency of activation of the RT and X-PDT mechanisms [18; 153]. The effective energy deposition in RT, together with the activation of the scintillating NPs and the trigger of the PS therapeutic effects in X-PDT, are key open question in nanosystems. In nanomedicine, the debate can regard the comprehension of the increase of X-rays absorption cross section, the effective energy release within the nanomaterials embedded in the biological surrounding, and the radiation dose-enhancement in the vicinity of the malignancy due to the presence of high-Z elements. The main goal of exploiting the passive NPs or single component active NPs is to increase the RT effects at the lowest doses in the disease site, and to localize the radiation energy deposition and RT damages only in the cancer site, while preserving from the radiation lethal toxicity the healthy tissue and organ in the patient [154; 155]. As discussed in Section 5, this point can be addressed by creating tumor-targeting NPs, such as NPs functionalized by folic acid, able to accumulate only in the cancer tissue and thus to locally increase the absorbed dose [93; 156]. Moreover, the question on the X-PDT processes in hybrids is under debate: here, besides the mechanism due to the presence of high-Z nanoscintillator, the effect of the photo-toxicity of the PS grafted on their surface should be considered, together with the possible interaction of the high energy beam directly with the PS. If on the one hand, different publications in the literature have demonstrated the occurrence of a synergetic effect given by the simultaneous application of the RT and the PDT in presence of PS grafted on NS [18; 152; 157], on the other hand the X-PDT phenomenology lacks unique explanation--i.e., whether the dominant therapeutic effect is due to the presence of high Z elements allowing for an enhancement of radiation dose deposition close to the injured tissues, or to the establishment of a tradeoff between the RT and PDT enabling simultaneously the reduction of the total dose to the patient and the induction of additional cell death mechanisms by toxic singlet oxygen moieties. In this context, Monte Carlo simulations are powerful tools enabling to properly connect the clinical beam simulations to the phenomena expected to occur at the NP level. Many Monte Carlo codes have been developed [158; 159] to explore the dose enhancement in RT, especially with X-ray beams, electron beams, and proton beams; each of these simulations helps to quantify the spatial energy distribution resulting from the interaction between the X-ray photon at diverse energies and the NP/NS, which finally drives the sensitization efficiency in RT and the activation of molecular singlet oxygen sensitizers in PDT and X-PDT. In addition, these computational studies allow to model the release of secondary particles after the first ionization event in relation to the nanomaterials physical, chemical, and structural properties. For instance, interesting computational studies have explored the use of passive high Z agents, like iodine, gadolinium, and gold, to treat human brain tumors in synchrotron stereotactic radiotherapy (SSRT) with irradiation by monochromatic X-rays from a synchrotron source, tuned at an optimal energy [160]. Especially, [PERSON] et al.