Med Phys. 2015 Nov;42(11):6703-10.

Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles.

Martínez-Rovira I, Prezado Y.

Laboratoire d’Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC), Centre National de la Recherche Scientifique (CNRS), Université Paris 7 and 11, Campus Universitaire, Bât. 440, 1er étage, 15 rue Georges Clemenceau, Orsay Cedex 91406, France.



PURPOSE: The outcome of radiotherapy can be further improved by combining irradiation with dose enhancers such as high-Z nanoparticles. Since 2004, spectacular results have been obtained when low-energy x-ray irradiations have been combined with nanoparticles. Recently, the same combination has been explored in hadron therapy. In vitro studies have shown a significant amplification of the biological damage in tumor cells charged with nanoparticles and irradiated with fast ions. This has been attributed to the increase in the ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement. However, this subject is still a matter of controversy. Within this context, the main goal of the authors’ work was to provide new insights into the dose enhancement effects of nanoparticles in proton therapy.

METHODS: For this purpose, Monte Carlo calculations (gate/geant4 code) were performed. In particular, the geant4-DNA toolkit, which allows the modeling of early biological damages induced by ionizing radiation at the DNA scale, was used. The nanometric radial energy distributions around the nanoparticle were studied, and the processes (such as Auger deexcitation or dissociative electron attachment) participating in the dose deposition of proton therapy treatments in the presence of nanoparticles were evaluated. It has been reported that the architecture of Monte Carlo calculations plays a crucial role in the assessment of nanoparticle dose enhancement and that it may introduce a bias in the results or amplify the possible final dose enhancement. Thus, a dosimetric study of different cases was performed, considering Au and Gd nanoparticles, several nanoparticle sizes (from 4 to 50 nm), and several beam configurations (source-nanoparticle distances and source sizes).

RESULTS: This Monte Carlo study shows the influence of the simulations’ parameters on the local dose enhancement and how more realistic configurations lead to a negligible increase of local energy deposition. The obtained dose enhancement factor was up to 1.7 when the source was located at the nanoparticle surface. This dose enhancement was reduced when the source was located at further distances (i.e., in more realistic situations). Additionally, no significant increase in the dissociative electron attachment processes was observed.

CONCLUSIONS: The authors’ results indicate that physical effects play a minor role in the amplification of damage, as a very low dose enhancement or increase of dissociative electron attachment processes is observed when the authors get closer to more realistic simulations. Thus, other effects, such as biological or chemical processes, may be mainly responsible for the enhanced radiosensibilization observed in biological studies. However, more biological studies are needed to verify this hypothesis.

PMID: 26520760



Radiotherapy (RT) is one of the main modalities for cancer treatment, its main limitation being the high morbidity of the surrounding healthy tissue. In recent years, the use of nanoparticles as potential tumour selective radiosensitizers has been proposed as a breakthrough in RT.

Nanoparticles can be preferentially delivered to the tumour through the enhanced permeability and retention effect (EPR). They are capable of penetrating the cell and they lead to fewer adverse effects than conventional radiosensitizers. However, radiation sensitivity using nanoparticles depends on nanoparticle type, cell line, irradiation energy, nanoparticle size, concentration and intracellular localization.

High-Z metallic nanoparticles (Au, Gd, Pt, Ag, Fe, etc.) have been preferentially used trying to exploit a possible enhanced generation of short-range photoelectrons or Auger electrons, which deposit the dose locally. The idea is to increase the effect in the tumour, while minimizing the normal tissue damage.

Since the pioneering experiment performed by Hainfeld et al. [1], numerous biological studies have shown a significant gain in tumour control when low-energy x-rays are delivered in the presence of nanoparticles (see [2-4], among others). However, the fact that studies using megavoltage beams [5-6] lead to comparable effects indicates that the radiosensitization effect of nanoparticles cannot be only attributed to physical effects (dose enhancement); biochemical processes induced by the nanoparticles inside the cells might have a non-negligible role. [7].

Despite extensive research on nanoparticle radiosensitization using photon beams, only a few experimental studies have been carried out using hadron beams [8-13]. In particular, experiments performed at the molecular scale (using plasmid DNA as a probe) have shown an amplification of damage in the presence of Pt NPs [8,9,13]. Additionally, Kim and collaborators have observed a fourfold reduction in tumour volume in the presence of gold and iron nanoparticles irradiated with 45 MeV protons [10,11]. Finally, Polf et al. have also reported an increase of effectiveness of around 10-15% when using gold nanoparticles and proton therapy in human prostate carcinoma cells [12].

The observed gain has been tentatively associated with the increase in ionizations and electron emissions induced by the incident ions or the electrons in the secondary tracks on the high-Z atoms, resulting in a local energy deposition enhancement [13]. However, the mechanisms involved have not been systematically investigated.

Two recent Monte Carlo studies have evaluated the local dose enhancement in the combination of proton therapy and nanoparticles [14,15]. Lin et al. observed significant dose enhancement factors (DEF) (up to 12) in the case of proton therapy combined with 50 nm Au nanoparticles [14]. In contrast, Walzlein et al. found a DEF that was remarkably lower (peaking at around two at the nanoparticle surface) for similar irradiation conditions [15]. Both works considered a direct frontal collision of protons with nanoparticles to save computation time. However, the architecture of Monte Carlo simulations may introduce a bias in the results that amplifies the possible final dose enhancement [16].

Along this line, the goal of this work was to evaluate how the dose enhancement varies as a function of the irradiation configuration. With this aim, Monte Carlo calculations (GATE/Geant4 code) were performed to assess the nanoparticle-induced dose enhancement in proton therapy for several conditions, including several nanoparticle types (Gd and Au) and diameters (4 and 50 nm), various distances source-nanoparticle (between 0 to 0.2 mm) and various source sizes (between 4-200 nm). The simulation scheme is represented in Figure 1.



fig1Figure 1. Nanometric simulations. Particles from the phase-space file (PSF) source model impinging on a nanoparticle (Gd/Au nanoparticles of 4/50 nm-diameter) surrounded by water. Geant4-DNA physical models used in the first shell of water, while ‘standard’-Geant4 physics lists were employed in the outer shell. The figures are not to scale.


A phase-space file source model was obtained recording the phase-space distributions of particles reaching the Bragg peak position originated from 200 MeV protons impinging on a water phantom. The information contained in the PSF (energy spectra and phase space distributions) was used to generate several particle sources with nanometric dimensions.

Results showed dose enhancement factors (DEF) up to 1.7 when the source was located at the nanoparticle surface. This dose enhancement was reduced when the source was located at further distances (i.e., in more realistic situations) and DEF values were non-equal to unity only in the first 1—3 nm from the nanoparticle surface.

Dissociative electron attachment processes were also evaluated since very low-energy electrons (below the ionization energy) may play a dominant role in cell damage by dissociative attachment. However, no significant increase in the dissociative electron attachment processes was observed for any studied case.

Thus, these results put in evidence the importance of the selection of the simulation parameters to assess dose distributions at a nanometric scale; different irradiation geometries could lead to different DEF values. The simulation of more realistic cases leads to a progressive reduction of local dose enhancement. This, added to the fact that the fluencies considered in the calculations are even higher that those in clinical treatments, suggests that physical effects play a minor role in the radiosensitization results reported in biological studies. Other effects, such as biological or chemical processes, may be a major contributor in the amplification of damage.



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