Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. I. Presentation and validation of a microdosimetric model.

A microdosimetric model that makes it possible to consider the numerous biological and physical parameters of cellular alpha-particle irradiation by radiolabeled mAbs was developed. It allows for the calculation of single-hit and multi-hit distributions of specific energy within a cell nucleus or a whole cell in any irradiation configuration. Cells are considered either to be isolated or to be packed in a monolayer or a spheroid. The method of calculating energy deposits is analytical and is based on the continuous-slowing-down approximation. A model of cell survival, calculated from the microdosimetric spectra and the microdosimetric radiosensitivity, z(0), was also developed. The algorithm of calculations was validated by comparison with two general Monte Carlo codes: MCNPX and Geant4. Microdosimetric spectra determined by these three codes showed good agreement for numerous geometrical configurations. The analytical method was far more efficient in terms of calculation time: A gain of more than 1000 was observed when using our model compared with Monte Carlo calculations. Good agreements were also observed with previously published results.

Evidence of extranuclear cell sensitivity to alpha-particle radiation using a microdosimetric model. II. Application of the microdosimetric model to experimental results.

A microdosimetric model was used to analyze the results of experimental studies on cells of two lymphoid cell lines (T2 and Ada) irradiated with (213)Bi-radiolabeled antibodies. These antibodies targeted MHC/peptide complexes. The density of target antigen could be modulated by varying the concentration of the peptide loaded onto the cells. This offered the possibility of changing the ratio of specific (from cell-bound antibody) to non-specific (from antibody present in the supernatant) irradiation. For both cell lines, survival plotted as a function of the mean absorbed dose was a decreasing exponential. For the T2 cells, the microdosimetric sensitivity calculated for the whole cell was equal whether the irradiation was non-specific (z(0) = 0.12 +/- 0.02 Gy) or specific (z(0) = 0.12 +/- 0.09 Gy). Similar results were obtained for Ada cells. These results constitute a biological validation of the microdosimetric model. For both cells, the measured cell mortality was greater than the percentage of hit cells calculated with the model at low mean absorbed doses. This observation thus suggests bystander effects. It poses the question of the relevance of the mean absorbed dose to the cell nuclei. A new concept in cellular dosimetry taking into account cytoplasm or membrane irradiation and bystander modeling appears to be needed.

Assessment of a fully 3D Monte Carlo reconstruction method for preclinical PET with iodine-124.

Iodine-124 is a radionuclide well suited to the labeling of intact monoclonal antibodies. Yet, accurate quantification in preclinical imaging with I-124 is challenging due to the large positron range and a complex decay scheme including high-energy gammas. The aim of this work was to assess the quantitative performance of a fully 3D Monte Carlo (MC) reconstruction for preclinical I-124 PET. The high-resolution small animal PET Inveon (Siemens) was simulated using GATE 6.1. Three system matrices (SM) of different complexity were calculated in addition to a Siddon-based ray tracing approach for comparison purpose. Each system matrix accounted for a more or less complete description of the physics processes both in the scanned object and in the PET scanner. One homogeneous water phantom and three heterogeneous phantoms including water, lungs and bones were simulated, where hot and cold regions were used to assess activity recovery as well as the trade-off between contrast recovery and noise in different regions. The benefit of accounting for scatter, attenuation, positron range and spurious coincidences occurring in the object when calculating the system matrix used to reconstruct I-124 PET images was highlighted. We found that the use of an MC SM including a thorough modelling of the detector response and physical effects in a uniform water-equivalent phantom was efficient to get reasonable quantitative accuracy in homogeneous and heterogeneous phantoms. Modelling the phantom heterogeneities in the SM did not necessarily yield the most accurate estimate of the activity distribution, due to the high variance affecting many SM elements in the most sophisticated SM.

Quantification of activity by alpha-camera imaging and small-scale dosimetry within ovarian carcinoma micrometastases treated with targeted alpha therapy.

Targeted alpha therapy (TAT) a promising treatment for small, residual, and micrometastatic diseases has questionable efficacy against malignant lesions larger than the α-particle range, and likely requires favorable intratumoral activity distribution. Here, we characterized and quantified the activity distribution of an alpha-particle emitter radiolabelled antibody within >100-µm micrometastases in a murine ovarian carcinoma model. Nude mice bearing ovarian micrometastases were injected intra-peritoneally with 211At-MX35 (total injected activity 6 MBq, specific activity 650 MBq/mg). Animals were sacrificed at several time points, and peritoneal samples were excised and prepared for alpha-camera imaging. Spatial and temporal activity distributions within micrometastases were derived and used for small-scale dosimetry. We observed two activity distribution patterns: uniform distribution and high stable uptake (>100% IA/g at all time points) in micrometastases with no visible stromal compartment, and radial distribution (high activity on the edge and poor uptake in the core) in tumor cell lobules surrounded by fibroblasts. Activity distributions over time were characterized by a peak (140% IA/g at 4 h) in the outer tumor layer and a sharp drop beyond a depth of 50 µm. Small-scale dosimetry was performed on a multi-cellular micrometastasis model, using time-integrated activities derived from the experimental data. With injected activity of 400 kBq, tumors exhibiting uniform activity distribution received <25 Gy (EUD=13 Gy), whereas tumors presenting radial activity distribution received mean absorbed doses of <8 Gy (EUD=5 Gy). These results provide new insight into important aspects of TAT, and may explain why micrometastases >100 µm might not be effectively treated by the examined regimen.