# Co-Adjuvant Nanoparticles for Radiotherapy Treatments of Oncological Diseases
## 5 Targeting Strategies for Enhancing NPs Sensitizing Effects  
Two important features are required to design effective nanotechnologies conceived for X-rays based oncological treatments: one is a selective tumor cell targeting and the other is a rapid clearance from human body after treatment [163; 164]. These achievements are highly dependent on the size of the nanomaterials that can affect the efficacy of the treatment reducing its side effects (such as undesirable ROS generation, disruption of cellular compartments, immune reactions, inflammation, destruction of the host homeostasis) [165; 166]: for instance, it has been reported that non-targeted heavy nanoparticles  
Figure 7: **(a,b)** Deposited energy per unit of normalized radial distance from the center of the NP (diameter of 100 nm of Gd\({}_{2}\)O\({}_{3}\)) for (1)—2 keV electrons and (2)—10 keV electrons. Visualization of the spatial distribution of the deposited energy is shown as insets. **(c)** Percentage of deposited energy per electron generated in a Gd\({}_{2}\)O\({}_{3}\) nanoparticle for three different diameters, as a function of the primary electron energy. Reproduced from _Nanoscale_**2015**, \(7\), 5744–5751 [162]. Copyright Royal Society of Chemistry 2015.  
with diameter \(\sim\)50 nm have the highest cellular uptake and are able to increase the efficacy of RT treatment [164, 167]. Thanks to their size, nanoparticles tend to accumulate more in tumor tissues with respect to the normal ones due to the enhanced permeability and retention (EPR) effect [168]. This passive targeting exploits the fact that tumors have a leaky vasculature, different pH, and different local temperature, and are devoid of an efficient lymphatic drainage system. Therefore, nanoparticles with suitable physico-chemical characteristics and size can extravasate from leaky tumor vessels and accumulate in the tumors [169]. Passive targeting, however, may induce multi-drug resistance (MDR), a poor drug diffusion, and a-specific accumulation in liver and spleen [163, 170]. One of the most promising approaches for improving the retention and accumulation of NPs in tumor cells relies on grafting the NPs surface with cancer cell-specific targeting ligands. Tumor accumulation of actively targeted nanoparticles has been found to be 5 times faster and approximately 2-fold higher than their passive counterparts, within the 60 nm diameter range [164]. Among the ligands used to target cancer cells we can mention antibodies, peptides, and aptamers to recognize and bind overexpressed cancer cell receptors (such as epidermal growth factor receptors), together with folate receptors and transferrin-receptors to enhance the cellular uptake of nanoparticles [171, 172, 173]. Some monoclonal antibodies have been exploited in strategies combining chemotherapeutic agents or immunotherapy with ionizing radiation; in vitro _and_ in vivo results have proven that antibodies promote and potentiate apoptosis and cytotoxic effects, thus damaging DNA of the cancer cells. Successful medical outcomes have been obtained especially for the treatment of breast cancer [174, 175, 176]. In this context, the human epidermal receptor-2 (HER-2) is the most widely studied overexpressed targeting receptor for therapeutic applications [177]. The most commonly ligand targeted to HER-2, is the anti-HER-2 mAb [178]. The functionalization of gold nanoclusters (AuNCs) with anti-HER2-mAb and/or folic acid (FA) as a single and dual-targeted radiosensitizers has shown the increasing of cellular internalization and of the RT efficiency (Figure 8) [179]. Despite the fact that just an exceedingly small amount of antibody is needed to target a specific site, the expensive production and immunogenic properties may restrain their applications in clinical trials [180].