Multi-cellular dosimetry of beta(+)-emitting radionuclides used for cell labeling in the context of cell tracking studies with PET imaging

Complete text of publication follows: Purpose: In vitro radiolabeling of cells combined with nuclear medicine imaging provides a potential method for in vivo cell trafficking analysis. Besides, the use of beta(+)-emitting radionuclides is of particular interest given the good intrinsic characteristics offered by PET technology. The labeling procedure still raises concerns regarding the high amount of radioactivity typically used which induces a cell cytotoxicity. Accurate dosimetry is required to allow for a better understanding of the toxicity associated to labeling. This work aimed to develop a realistic multi-cellular dosimetry and apply the model to the analysis of 3 radionuclides used for labeling in PET: ¹⁸F, ⁶⁴Cu and ⁶⁸Ga. Methods: A program using Python was developed to generate cell coordinates from a set of initial parameters i.e. cell size, cell density, bounding volume size. A cubic cell arrangement was assumed and the calculation approach was based on an analytical formula using derived-Monte Carlo S factors. Both the contribution to the dose of radioactivity located within the cells and in the culture medium were considered. The mean absorbed dose to cells was evaluated as a function of the cell density and the intra-to-extra cellular activity repartition. The results were compared with those obtained using conventional dosimetry. Dose calculations were also done under realistic conditions of leukocytes labeling with ¹⁸F -FDG based on labeling parameters used in few reported studies. Results: The cellular-to-conventional dose ratios can vary significantly with cell density, reaching important values at low density and approaching 1 at high density. They were also influenced by the activity repartition between the cells and the medium, the highest values occurring when all activity was incorporated in the cells. A significant underestimation of mean dose to the cell by conventional model was particularly observed for ⁶⁴Cu up to a factor of 15 at low density, due to the emission of short-range auger electrons. ⁶⁸Ga and ¹⁸F presented lower discrepancies between cellular and conventional doses considering the emission of larger-range beta(+). The calculations done for labeling conditions taken from literature showed that a same injected activity per cell can result in significantly different absorbed doses. Conclusions: The development of a realistic multi-cellular dosimetry offered a better understanding of how absorbed dose to cell is affected as a function of key labeling parameters. The establishment of the dose-effect correlation for mesenchymal stem cells is under way through functional tests in vitro after labeling with ¹⁸F-FDG and external irradiation for comparison