title: Cell-specific radiosensitization by gold nanoparticles at megavoltage radiation energies.
abstract: OBJECTIVE
  Gold nanoparticles (GNPs) have been shown to cause sensitization with kilovoltage (kV) radiation. Differences in the absorption coefficient between gold and soft tissue, as a function of photon energy, predict that maximum enhancement should occur in the kilovoltage (kV) range, with almost no enhancement at megavoltage (MV) energies. Recent studies have shown that GNPs are not biologically inert, causing oxidative stress and even cell death, suggesting a possible biological mechanism for sensitization. The purpose of this study was to assess GNP radiosensitization at clinically relevant MV X-ray energies.
  
  
  METHODS
  Cellular uptake, intracellular localization, and cytotoxicity of GNPs were assessed in normal L132, prostate cancer DU145, and breast cancer MDA-MB-231 cells. Radiosensitization was measured by clonogenic survival at kV and MV photon energies and MV electron energies. Intracellular DNA double-strand break (DSB) induction and DNA repair were determined and GNP chemosensitization was assessed using the radiomimetic agent bleomycin.
  
  
  RESULTS
  GNP uptake occurred in all cell lines and was greatest in MDA-MB-231 cells with nanoparticles accumulating in cytoplasmic lysosomes. In MDA-MB-231 cells, radiation sensitizer enhancement ratios (SERs) of 1.41, 1.29, and 1.16 were achieved using 160 kVp, 6 MV, and 15 MV X-ray energies, respectively. No significant effect was observed in L132 or DU145 cells at kV or MV energies (SER 0.97-1.08). GNP exposure did not increase radiation-induced DSB formation or inhibit DNA repair; however, GNP chemosensitization was observed in MDA-MB-231 cells treated with bleomycin (SER 1.38).
  
  
  CONCLUSIONS
  We have demonstrated radiosensitization in MDA-MB-231 cells at MV X-ray energies. The sensitization was cell-specific with comparable effects at kV and MV energies, no increase in DSB formation, and GNP chemopotentiation with bleomycin, suggesting a possible biological mechanism of radiosensitization.
authors.affiliation: Northern Ireland Cancer Centre, Queen's University, Belfast, Northern Ireland. suneiljain@hotmail.com
authors.forename: Suneil
authors.initials: S
authors.lastname: Jain
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coulter
authors.forename: Alan R
authors.initials: AR
authors.lastname: Hounsell
authors.forename: Karl T
authors.initials: KT
authors.lastname: Butterworth
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: McMahon
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Hyland
authors.forename: Mark F
authors.initials: MF
authors.lastname: Muir
authors.forename: Glenn R
authors.initials: GR
authors.lastname: Dickson
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Prise
authors.forename: Fred J
authors.initials: FJ
authors.lastname: Currell
authors.forename: Joe M
authors.initials: JM
authors.lastname: O'Sullivan
authors.forename: David G
authors.initials: DG
authors.lastname: Hirst
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy; D002453:Cell Cycle / Q000528:radiation effects; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000528:radiation effects; D005260:Female; D006046:Gold / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D053768:Metal Nanoparticles / Q000627:therapeutic use*; D046529:Microscopy, Electron, Transmission; D009928:Organ Specificity; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000187:drug effects / Q000528:radiation effects*; D011882:Radiotherapy, High-Energy / Q000379:methods*; D014410:Tumor Stem Cell Assay / Q000379:methods
chemical_list: D000903:Antibiotics, Antineoplastic; D004273:DNA, Neoplasm; D001761:Bleomycin; D006046:Gold