Article Figures & Data
Figures
- FIGURE 1.
Cellular morphologies. (A) 4Pi confocal microscope images with corresponding polygonal mesh structures. (B) Example of cell population representing modeled planar cellular cluster in Geant 4 (perspective view) where all cells are identical. Nucleus, G, and Cy are represented in blue/purple, green, and red, respectively. Cell population models reproduce confluence level of 50% ± 5%, estimated from radiobiologic observations. Geometric characteristics of the 3 cells are reported in Table 1.
- FIGURE 2.
Immunofluorescent staining of U2OS-SSTR2 cells and corresponding simulation hypotheses. (A) From left to right, images report nucleus, G, and SSTR2 stainings for untreated cells (top) and cells incubated with DOTATATE (bottom). Merged image at end highlights colocalization of SSTR2 with G after 1 h of incubation with DOTATATE. Scale bar = 5 µm. (B) Example of internalized source simulation for cell morphology 2. Nucleus, G, and Cy are reported in green, light blue, and light gray, respectively. Electron tracks are drawn in red, with yellow energy deposition points, which become blue when traversing nucleus.
- FIGURE 3.
Comparison between probabilities (A) and number (B) of SPs entering nucleus for 3 cell models, as indicated by x-axis, and the 3 source localizations (Cy, G [including contribution of CM], and medium when comparable to cell sources), including planar cross-irradiation. Number of particles entering nucleus refers to 2.5 MBq/mL of added activity to which experimental data correspond. Medium contribution is assumed to be same for the 3 morphologies on basis of simulations for cell 1. Each graph is subdivided into 2 windows corresponding to the 2 emission types (β and IC), as indicated by titles. N = nucleus.
- FIGURE 4.
Simulation results and graphical explanation. (A) DSB-yield (DSBs/Gbp SP) comparison for the 3 cell morphologies (as indicated by x-axis), the 3 source localizations (Cy, G [including contribution of CM], and medium), and the 2 emission types. Medium contribution is assumed to be same for the 3 morphologies on basis of simulations for cell 1. (B) Total nucleus irradiation (i.e., self- and cross-irradiation) characterizing nucleus 3 when IC electrons are emitted from G. (C) Total nucleus irradiation (i.e., self- and cross-irradiation) characterizing nucleus 1 when IC electrons are emitted from G. Color bars indicate energy (keV) at entrance of nucleus.
- FIGURE 5.
Energy spectra of electrons entering nucleus of the 3 cell morphologies. (A) Distributions corresponding to β particles. (B) Distributions corresponding to IC electrons. Each color corresponds to the 3 source localizations (Cy, G [including contribution of CM], and medium). Dotted lines indicate mean value of energy spectra. Spectrum of medium is assumed to be same as cell 1 for the 3 morphologies and is replicated in each graph for comparison with cell sources. Energy bin is 10 keV.
- FIGURE 6.
Probability density functions of energy deposited per particle in nucleus of the 3 cell morphologies. Each distribution corresponds to the 3 source localizations (Cy, G [including contribution of CM], and medium) and the 2 emission types (β and IC). Dotted lines indicate mean value of microscopic energy distributions, from which mean specific energy (
) is evaluated (Table 2). Spectrum of medium is assumed to be same as cell 1 for the 3 morphologies and is replicated in each graph for comparison with cell sources. - FIGURE 7.
DSB simulations, comparison with experimental data, and correlation with absorbed dose to nucleus. (A) Simulated number of DSBs per nucleus corresponding to the 3 cell morphologies and internalization hypotheses (Cy vs. G, including CM), indicating contribution of each particle type (β and IC electrons). (B) Simulated DSBs per nucleus corresponding to the 3 cell morphologies and internalization hypotheses (Cy vs. G, including CM), indicating contribution of medium or cell source (internalized and membrane-bound). (C) Frequency histogram of experimental number of DSBs per nucleus induced by 4 h of administration of 2.5 MBq/mL activity of 177Lu-DOTATATE, measured by 53BP1. (D) Linear correlations between absorbed dose to nuclei and simulated number of DSBs when internalized source is located in Cy and in G. DAPI = 4′,6-diamidino-2-phenylindole.
Tables
Volume (μm3) Parameter Cell 1 Cell 2 Cell 3 Cy 3,465.64 1,876.58 4,228.08 G 68.46 24.34 63.18 Nucleus 811.79 714.71 1,105.84 Size* (μm) Cy Bounding box: x = 72.24, y = 31.78, z = 5.99 Bounding box: x = 99.21, y = 30.86, z = 3.52 Bounding box: x = 88.70, y = 64.28, z = 6.29 Nucleus Ellipsoid: a = 12, b = 8.5, c = 1.9 Elliptic cylinder: a = 13, b = 7, c = 1.25 Elliptic cylinder: a = 8, b = 11, c = 2 * Reported in half-dimensions for nucleus.
CM thickness = 0.0075 μm (42,43).
- (Gy)
Parameter Cell 1 Cell 2 Cell 3 Cy β 1.24 0.99 1.27 G β 1.29 1.10 0.92 Cy IC 1.20 1.02 1.36 G IC 1.44 1.20 0.94 Medium β 0.52 Medium IC 0.69 Medium values (β and IC electrons) are calculated for nucleus 1 and assumed same for the 3 morphologies.
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