title: Effect of gadolinium-based nanoparticles on nuclear DNA damage and repair in glioblastoma tumor cells.
abstract: BACKGROUND
  Tumor targeting of radiotherapy represents a great challenge. The addition of multimodal nanoparticles, such as 3 nm gadolinium-based nanoparticles (GdBNs), has been proposed as a promising strategy to amplify the effects of radiation in tumors and improve diagnostics using the same agents. This singular property named theranostic is a unique advantage of GdBNs. It has been established that the amplification of radiation effects by GdBNs appears due to fast electronic processes. However, the influence of these nanoparticles on cells is not yet understood. In particular, it remains dubious how nanoparticles activated by ionizing radiation interact with cells and their constituents. A crucial question remains open of whether damage to the nucleus is necessary for the radiosensitization exerted by GdBNs (and other nanoparticles).
  
  
  METHODS
  We studied the effect of GdBNs on the induction and repair of DNA double-strand breaks (DSBs) in the nuclear DNA of U87 tumor cells irradiated with γ-rays. For this purpose, we used currently the most sensitive method of DSBs detection based on high-resolution confocal fluorescence microscopy coupled with immunodetection of two independent DSBs markers.
  
  
  RESULTS
  We show that, in the conditions where GdBNs amplify radiation effects, they remain localized in the cytoplasm, i.e. do not penetrate into the nucleus. In addition, the presence of GdBNs in the cytoplasm neither increases induction of DSBs by γ-rays in the nuclear DNA nor affects their consequent repair.
  
  
  CONCLUSIONS
  Our results suggest that the radiosensitization mediated by GdBNs is a cytoplasmic event that is independent of the nuclear DNA breakage, a phenomenon commonly accepted as the explanation of biological radiation effects. Considering our earlier recognized colocalization of GdBNs with the lysosomes and endosomes, we revolutionary hypothesize here about these organelles as potential targets for (some) nanoparticles. If confirmed, this finding of cytoplasmically determined radiosensitization opens new perspectives of using nano-radioenhancers to improve radiotherapy without escalating the risk of pathologies related to genetic damage.
authors.affiliation: Department of Cell Biology and Radiobiology, Institute of Biophysics of ASCR, Brno, Czech Republic. lenka.stefancikova@u-psud.fr.|Institute des Sciences Moléculaires d'Orsay (ISMO), Université Paris Sud 11, CNRS, Université Paris Saclay, Bât 351, 91405, Orsay Cedex, France. lenka.stefancikova@u-psud.fr.
authors.forename: Lenka
authors.identifier: http://orcid.org/0000-0003-1644-0353
authors.initials: L
authors.lastname: Štefančíková
authors.affiliation: Institute des Sciences Moléculaires d'Orsay (ISMO), Université Paris Sud 11, CNRS, Université Paris Saclay, Bât 351, 91405, Orsay Cedex, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lacombe
authors.affiliation: Institute des Sciences Moléculaires d'Orsay (ISMO), Université Paris Sud 11, CNRS, Université Paris Saclay, Bât 351, 91405, Orsay Cedex, France.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salado
authors.affiliation: Institute des Sciences Moléculaires d'Orsay (ISMO), Université Paris Sud 11, CNRS, Université Paris Saclay, Bât 351, 91405, Orsay Cedex, France.
authors.forename: Erika
authors.initials: E
authors.lastname: Porcel
authors.affiliation: Department of Cell Biology and Radiobiology, Institute of Biophysics of ASCR, Brno, Czech Republic.
authors.forename: Eva
authors.initials: E
authors.lastname: Pagáčová
authors.affiliation: Institut Lumière Matière, Université Claude Bernard Lyon 1, CNRS, 69622, Villeurbanne Cedex, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Tillement
authors.affiliation: Institut Lumière Matière, Université Claude Bernard Lyon 1, CNRS, 69622, Villeurbanne Cedex, France.
authors.forename: François
authors.initials: F
authors.lastname: Lux
authors.affiliation: Department of Cell Biology and Radiobiology, Institute of Biophysics of ASCR, Brno, Czech Republic.
authors.forename: Daniel
authors.initials: D
authors.lastname: Depeš
authors.affiliation: Department of Cell Biology and Radiobiology, Institute of Biophysics of ASCR, Brno, Czech Republic.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Kozubek
authors.affiliation: Department of Cell Biology and Radiobiology, Institute of Biophysics of ASCR, Brno, Czech Republic. falk@ibp.cz.
authors.forename: Martin
authors.initials: M
authors.lastname: Falk
mesh_terms: D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D005682:Gadolinium / Q000633:toxicity*; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D053768:Metal Nanoparticles / Q000633:toxicity*
chemical_list: D005682:Gadolinium
keywords: DNA double-strand breaks; DNA repair; Gadolinium; Nanomedicine; Nanoparticles; Radiosensitization; Radiotherapy; Theranostic