title: Monte Carlo N-Particle (MCNP) Modeling of the Cellular Dosimetry of 64Cu: Comparison with MIRDcell S Values and Implications for Studies of Its Cytotoxic Effects.
abstract: 64Cu emits positrons as well as β-particles and Auger and internal conversion electrons useful for radiotherapy. Our objective was to model the cellular dosimetry of64Cu under different geometries commonly used to study the cytotoxic effects of64Cu.
  
  
  METHODS
  Monte Carlo N-Particle (MCNP) was used to simulate the transport of all particles emitted by64Cu from the cell surface (CS), cytoplasm (Cy), or nucleus (N) of a single cell; monolayer in a well (radius = 0.32-1.74 cm); or a sphere (radius = 50-6,000 μm) of cells to calculate S values. The radius of the cell and N ranged from 5 to 12 μm and 2 to 11 μm, respectively. S values were obtained by MIRDcell for comparison. MCF7/HER2-18 cells were exposed in vitro to64Cu-labeled trastuzumab. The subcellular distribution of64Cu was measured by cell fractionation. The surviving fraction was determined in a clonogenic assay.
  
  
  RESULTS
  The relative differences of MCNP versus MIRDcell self-dose S values (Sself) for64Cu ranged from -0.2% to 3.6% for N to N (SN←N), 2.3% to 8.6% for Cy to N (SN←Cy), and -12.0% to 7.3% for CS to N (SN←CS). The relative differences of MCNP versus MIRDcell cross-dose S values were 25.8%-30.6% for a monolayer and 30%-34% for a sphere, respectively. The ratios of SN←Nversus SN←Cyand SN←Cyversus SN←CSdecreased with increasing ratio of the N of the cell versus radius of the cell and the size of the monolayer or sphere. The surviving fraction of MCF7 /: HER2-18 cells treated with64Cu-labeled trastuzumab (0.016-0.368 MBq/μg, 67 nM) for 18 h versus the absorbed dose followed a linear survival curve with α = 0.51 ± 0.05 Gy-1and R2= 0.8838. This is significantly different from the linear quadratic survival curve of MCF7 /: HER2-18 cells exposed to γ-rays.
  
  
  CONCLUSIONS
  MCNP- and MIRDcell-calculated S values agreed well.64Cu in the N increases the dose to the N in isolated single cells but has less effect in a cell monolayer or small cluster of cells simulating a micrometastasis, and little effect in a sphere analogous to a tumor xenograft compared with64Cu in the Cy or on the CS. The dose deposited by64Cu is less effective for cell killing than γ-rays.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yongkyu Luke
authors.initials: YL
authors.lastname: Kwon
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada raymond.reilly@utoronto.ca.|Department of Medical Imaging, University of Toronto, Toronto, Ontario, Canada.|Toronto General Research Institute, Toronto, Ontario, Canada; and.|Joint Department of Medical Imaging, University Health Network, Toronto, Ontario, Canada.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Reilly
mesh_terms: D065638:Absorption, Radiation; D002468:Cell Physiological Phenomena / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects*; D003198:Computer Simulation; D003301:Copper Radioisotopes / Q000008:administration & dosage* / Q000032:analysis*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D061986:MCF-7 Cells; D008954:Models, Biological; D015233:Models, Statistical; D009010:Monte Carlo Method; D011829:Radiation Dosage; D011874:Radiometry / Q000379:methods*; D012542:Scattering, Radiation
chemical_list: D003301:Copper Radioisotopes
keywords: 64Cu; MCNP; MIRDcell; dosimetry; theranostics