title: Evaluation of the local dose enhancement in the combination of proton therapy and nanoparticles.
abstract: OBJECTIVE
  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.
authors.affiliation: 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.
authors.forename: I
authors.initials: I
authors.lastname: Martínez-Rovira
authors.affiliation: 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.
authors.forename: Y
authors.initials: Y
authors.lastname: Prezado
mesh_terms: D003131:Combined Modality Therapy / Q000379:methods; D003198:Computer Simulation; D005682:Gadolinium; D006046:Gold; D053768:Metal Nanoparticles / Q000627:therapeutic use*; D009010:Monte Carlo Method; D010316:Particle Size; D019047:Phantoms, Imaging; D061766:Proton Therapy / Q000295:instrumentation / Q000379:methods*; D011879:Radiotherapy Dosage; D014867:Water
chemical_list: D014867:Water; D006046:Gold; D005682:Gadolinium