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

Cu-64 emits positrons as well as beta(-) particles and Auger and internal conversion electrons useful for radiotherapy. Our objective was to model the cellular dosimetry of Cu-64 under different geometries commonly used to study the cytotoxic effects of Cu-64. Methods: Monte Carlo N-Particle (MCNP) was used to simulate the transport of all particles emitted by Cu-64 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 mu m) of cells to calculate S values. The radius of the cell and N ranged from 5 to 12 mu m and 2 to 11 mu m, respectively. S values were obtained by MIRDcell for comparison. MCF7/HER2-18 cells were exposed in vitro to Cu-64-labeled trastuzumab. The subcellular distribution of Cu-64 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 (S-seif) for Cu-64 ranged from -0.2% to 3.6% for N to N (S-N <- N), 2.3% to 8.6% for Cy to N (S-N <- Cy), and -12.0% to 7.3% for CS to N (S-N <- 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 S-N <- N versus S-N <- Cy and S-N <- Cy versus S-N <- CS decreased 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 with Cu-64-labeled trastuzumab (0.016-0.368 MBq/mu g, 67 nM) for 18 h versus the absorbed dose followed a linear survival curve with alpha = 0.51 +/- 0.05 Gy(-1) and R-2 = 0.8838. This is significantly different from the linear quadratic survival curve of MCF7/HER2-18 cells exposed to gamma-rays. Conclusion: MCNP- and MIRD-cell-calculated S values agreed well. Cu-64 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 with Cu-64 in the Cy or on the CS. The dose deposited by Cu-64 is less effective for cell killing than gamma-rays.