Modelling of the nanoscopic mechanisms involved in nanoparticle induced radio-enhancement was first undertaken in the case of photon irradiation. The amplification of radiation effects in this case was explained in terms of a nanoscale enhancement of the local dose in close vicinity to the NPs. This was demonstrated by McMahon et al. (2011) and recently refined by Brown and Currell (2017), thus explaining the results of several experiments through adapting the Local Effect Model (LEM) (Scholz and Kraft 1996) initially developed for ion beams. This model, in its simpler formulation (LEM I), predicts a higher cell killing for higher densely ionizing (LET) radiation, correlating a higher spatial concentration of ionizations on a biological target, and then the induction of more severe damage to a higher probability to induce a lethal effect and than cell death. It was seen that simply including the high local enhancement of the dose due to Auger electrons can lead to a significant effect on the radial dose, which then induces an increase in cell killing quantified by a Sensitizing Enhancement Ratio (SER), i.e. a ratio of doses giving the same biological effect with and without sensitizer, in a way similar to an RBE (McMahon et al. 2011).
In the case of ion beam irradiation, an enhancement of radiation effects was observed in the presence of nanoparticles either at the molecular (DNA damage), in vitro (cell killing) and in vivo (mouse tumour regression) levels, as discussed in the previous section and listed in Table 1. However, the mechanistic explanation of local dose enhancement provided for photons is not the same as for ions. In the studies with photons, it was shown that a large increase in the radial dose profile was induced in the presence of NP as compared to photon irradiation in water, enough to justify the sizeable difference in the yield of severe damage. However, in the case of ions, the dose is already highly localized along the tracks, and an extremely high local dose would be required to induce an additional impact on the damage concentration, without even accounting for over-kill effects. In this case, the enhancement of radiation effects is not, as yet, fully understood. The first study approaching this problem (Wälzlein et al. 2014) was conducted using the particle track structure code TRAX (Krämer and Kraft 1994) to analyse, at a nanoscale level, a possible dose enhancement in high-Z nanoparticles (Au, Pt, Ag, Fe and Gd) traversed by proton beam (see Fig. 4). It was found that a relevant increase in local dose around the nanoparticle could be computed, but the relative enhancement was much smaller than that observed in photon irradiation. Moreover, the simulation was performed in the condition of ion traversing across the nanoparticle, which with typical fluences adopted in proton therapy (106 to 109 cm−2) is very rare. Thus, the dose enhancement effect occurring in the case of an ion traversal should be weighted by this very low probability to occur (≈10−3 to 10−4). In total, this would lead to a noticeably reduced overall dose enhancement effect. This study has shown a larger effect of gold and platinum, as compared to other high-Z materials, in acting as dose enhancers. More importantly, it demonstrated that, for proton radiation, a significant dose enhancement effect can be observed, mostly due to Auger electrons and consecutive cascades. However, this process is not sufficient to justify any overall macroscopic effect such as those observed in several experiments.
The amplification effect of ion radiation by high-Z NPs may be explained by other mechanisms, such as modification of the radiation chemistry pathways and enhancement of radical mediated component of radiation damage, as suggested with X-rays (Sicard-Roselli et al. 2014).
Gao and Zheng (2014) explored different proton energies and found that a larger number of electrons escape the nanoparticles for lower primary ion energy. These electrons have lower energies and shorter ranges compared to those induced by more energetic protons (Gao and Zheng 2014). Lin et al. (2014) attempted to establish comparative figures of merit between protons and different types of photon radiation (Lin et al. 2014) and proposed a model for biological effect calculation (Lin et al. 2015) based on the Local Effect Model. The result pointed out the need of a much higher nanoparticle uptake in the case of protons as compared to photons, in order to observe a similar enhancement effect. This concentration should be even higher for protons of lower energies for the emitted electrons of lower range to reach and affect sensitive cell components.
Verkhovtsev et al. (2015a, b) proposed the idea of a new channel through surface plasmon excitation, which was shown to strongly link to a large production of secondary electrons, thus arguing a new pathway for dose enhancement [Verkhovtsev et al. (2015a, b]. The authors showed, for 1 MeV protons, an increase of an order of magnitude in the emitted electron spectra, as compared to direct ionization.
Other studies, using Monte Carlo calculations, have been performed focusing on macroscopic dose enhancement due to the absorbed physical dose only (Ahmad et al. 2016; Cho et al. 2016). The effect was found to be very small for realistic values of NP concentrations.
A recent study (Martínez-Rovira and Prezado 2015) confirmed that a nanoscale dose enhancement, based on physical boost of electron production alone, cannot explain the amplification effect observed in experiments and that radiation chemistry or biological pathways should also be taken into account (Wälzlein et al. 2014). A critical summary of Monte Carlo studies on proton interaction with NP has been collected in Verkhovtsev et al. (2017).
A recent study attempted to include the physico-chemical and chemical stage in this process for protons of 2 to 170 MeV traversing a gold NP, using a combination of GEANT4 and GEANT4-DNA (Tran et al. 2016). Despite the underestimation of secondary electrons production at low energy inherent to the model, this study emphasized an interesting “radiolysis enhancement factor “, i.e., an increased radical production due the presence of the gold NP, which increases with the energy of the incident particle.
In Fig. 5, we show a scheme that summarizes all the mechanisms proposed in these studies.
Thus, despite the fact that several questions have been answered, modelling of the enhancement of ion beam effects with NPs is just at its initial stage. There is a large need for further studies. In particular, before entering the radiobiological effects, the first parameters to be verified are the cross sections of the pure physical processes, which are needed in the simulation codes. While many studies are focused on detecting a biological effect, the physics itself has still to be fully elucidated. For example, both elastic and inelastic cross sections in high-Z materials like gold have still not been characterized in detail, and relevant differences appear, e.g. when using the standard Livermore library (Wälzlein et al. 2014). Studies in this direction are now ongoing, providing, for the moment, a partial confirmation of the validity of the cross section sets used in TRAX (Hespeels et al. 2017).
As for the search of the ideal conditions of radio-enhancement, only effects of incident protons have been simulated, and there is no indication of a possible trend of the track structure effect, thus emphasizing an ion type dependence (beyond pure LET), as has been demonstrated for the RBE (Friedrich et al. 2013). As for the pure energy (or LET) dependence, despite some indications, there is still not a complete explanation of the enhancement effect. In particular, from experiments, this dependence appears counter-intuitive, pointing to a larger effect for higher LET, while one should expect a larger enhancement for a more “photon-like” radiation type. The challenges arising from these studies will probably stimulate research not only to shed light on the specific mechanism, but also on reconsidering the general paradigm of radiation bio-damage (Scifoni 2015).
In addition, the role of oxygenation of the medium (quantified by the Oxygen Enhancement Ratio—OER) may be significant. The OER with ion beams shows a strong peculiarity, decreasing with high LET (Furusawa et al. 2000). Thus far, the OER effect associated with the presence of nanoparticles has not yet been considered, aside from a study with photons where anoxic cells appeared to be not sensitized by NPs (Jain et al. 2014). However, this effect could be different with ion beams, and the potential to additionally sensitize hypoxic cells with NPs is very attractive. Last, but not least, it will be necessary to explicitly study the case of radio-enhancement mediated by NPs in the cytoplasm. In fact, as discussed above, it is now almost established, from most of the prior studies, that the enhancement of cell killing is induced by nanosensitisers located in the cytoplasm (Usami et al. 2008b; Porcel et al. 2010; Stefančíková et al. 2014), despite the fact that, as mentioned in the previous section, a few studies have also found NPs in the nucleus (Li et al. 2016). This type of study was initiated for photons, pointing to mitochondria as possible sensitive targets (McMahon et al. 2017). In the case of ions, these targets will have a completely different and probably more complex scenarios.