RESUMEN
Early use of targeted radionuclide therapy (TRT) to eradicate disseminated tumor cells (DTCs) might offer cure. Selection of appropriate radionuclides is required. This work highlights the potential of 103Pd (T1/2 = 16.991 d) which decays to 103mRh (T1/2 = 56.12 min) then to stable 103Rh with emission of Auger and conversion electrons. Methods: The Monte Carlo track structure code CELLDOSE was used to assess absorbed doses in single cells (14-µm diameter; 10-µm nucleus) and clusters of 19 cells. The radionuclide was distributed on the cell surface, within the cytoplasm, or in the nucleus. Absorbed doses from 103Pd, 177Lu and 161Tb were compared after energy normalization. The impact of non-uniform cell targeting, and the potential benefit from dual-targeting was investigated. Additional results related to 103mRh, if used directly, are provided. Results: In the single cell, and depending on radionuclide distribution, 103Pd delivered 7- to 10-fold higher nuclear absorbed dose and 9- to 25-fold higher membrane dose than 177Lu. In the 19-cell clusters, 103Pd absorbed doses also largely exceeded 177Lu. In both situations, 161Tb stood in-between 103Pd and 177Lu. Non-uniform targeting, considering four unlabeled cells within the cluster, resulted in moderate-to-severe dose heterogeneity. For example, with intranuclear 103Pd, unlabeled cells received only 14% of the expected nuclear dose. Targeting with two 103Pd-labeled radiopharmaceuticals minimized dose heterogeneity. Conclusion: 103Pd, a next-generation Auger emitter, can deliver substantially higher absorbed doses than 177Lu to single tumor cells and cell clusters. This may open new horizons for the use of TRT in adjuvant or neoadjuvant settings, or for targeting minimal residual disease.
Asunto(s)
Paladio , Radioisótopos , Paladio/química , Paladio/uso terapéutico , Paladio/administración & dosificación , Radioisótopos/uso terapéutico , Radioisótopos/farmacocinética , Humanos , Lutecio/uso terapéutico , Método de Montecarlo , Neoplasias/radioterapiaRESUMEN
BACKGROUND: Monte Carlo simulations have been considered for a long time the gold standard for dose calculations in conventional radiotherapy and are currently being applied for the same purpose in innovative radiotherapy techniques such as targeted radionuclide therapy (TRT). PURPOSE: We present in this work a benchmarking study of the latest version of the Transport d'Ions Lourds Dans l'Aqua & Vivo (TILDA-V ) Monte Carlo track structure code, highlighting its capabilities for describing the full slowing down of α $\alpha$ -particles in water and the energy deposited in cells by α $\alpha$ -emitters in the context of TRT. METHODS: We performed radiation transport simulations of α $\alpha$ -particles (10 keV u - 1 ${\rm u}^{-1}$ -100 MeV u - 1 ${\rm u}^{-1}$ ) in water with TILDA-V and the Particle and Heavy Ion Transport code System (PHITS) version 3.33. We compared the predictions of each code in terms of track parameters (stopping power, range and radial dose profiles) and cellular S-values of the promising radionuclide astatine-211 ( 211 At $^{211}{\rm At}$ ). Additional comparisons were made with available data in the literature. RESULTS: The stopping power, range and radial dose profiles of α $\alpha$ -particles computed with TILDA-V were in excellent agreement with other calculations and available data. Overall, minor differences with PHITS were ascribed to phase effects, that is, related to the use of interaction cross sections computed for water vapor or liquid water. However, important discrepancies were observed in the radial dose profiles of monoenergetic α $\alpha$ -particles, for which PHITS results showed a large underestimation of the absorbed dose compared to other codes and experimental data. The cellular S-values of 211 At $^{211}{\rm At}$ computed with TILDA-V agreed within 4% with the values predicted by PHITS and MIRDcell. CONCLUSIONS: The validation of the TILDA-V code presented in this work opens the possibility to use it as an accurate simulation tool for investigating the interaction of α $\alpha$ -particles in biological media down to the nanometer scale in the context of medical research. The code may help nuclear medicine physicians in their choice of α $\alpha$ -emitters for TRT. Further research will focus on the application of TILDA-V for quantifying radioinduced damage on the deoxyribonucleic acid (DNA) molecule.
Asunto(s)
Partículas alfa , Astato , Método de Montecarlo , Radiometría , Radiometría/métodos , Partículas alfa/uso terapéutico , Astato/uso terapéutico , Humanos , Dosificación RadioterapéuticaRESUMEN
Early use of targeted radionuclide therapy to eradicate tumor cell clusters and micrometastases might offer cure. However, there is a need to select appropriate radionuclides and assess the potential impact of heterogeneous targeting. Methods: The Monte Carlo code CELLDOSE was used to assess membrane and nuclear absorbed doses from 177Lu and 161Tb (ß--emitter with additional conversion and Auger electrons) in a cluster of 19 cells (14-µm diameter, 10-µm nucleus). The radionuclide distributions considered were cell surface, intracytoplasmic, or intranuclear, with 1,436 MeV released per labeled cell. To model heterogeneous targeting, 4 of the 19 cells were unlabeled, their position being stochastically determined. We simulated situations of single targeting, as well as dual targeting, with the 2 radiopharmaceuticals aiming at different targets. Results: 161Tb delivered 2- to 6-fold higher absorbed doses to cell membranes and 2- to 3-fold higher nuclear doses than 177Lu. When all 19 cells were targeted, membrane and nuclear absorbed doses were dependent mainly on radionuclide location. With cell surface location, membrane absorbed doses were substantially higher than nuclear absorbed doses, both with 177Lu (38-41 vs. 4.7-7.2 Gy) and with 161Tb (237-244 vs. 9.8-15.1 Gy). However, when 4 cells were not targeted by the cell surface radiopharmaceutical, the membranes of these cells received on average only 9.6% of the 177Lu absorbed dose and 2.9% of the 161Tb dose, compared with a cluster with uniform cell targeting, whereas the impact on nuclear absorbed doses was moderate. With an intranuclear radionuclide location, the nuclei of unlabeled cells received only 17% of the 177Lu absorbed dose and 10.8% of the 161Tb dose, compared with situations with uniform targeting. With an intracytoplasmic location, nuclear and membrane absorbed doses to unlabeled cells were one half to one quarter those obtained with uniform targeting, both for 177Lu and for 161Tb. Dual targeting was beneficial in minimizing absorbed dose heterogeneities. Conclusion: To eradicate tumor cell clusters, 161Tb may be a better candidate than 177Lu. Heterogeneous cell targeting can lead to substantial heterogeneities in absorbed doses. Dual targeting was helpful in reducing dose heterogeneity and should be explored in preclinical and clinical studies.