Victor Levrague

Mario Alcocer-Avila

Sarah Otmani

Lydia Maigne

Etienne Testa

Michaël Beuve

Rachel Delorme

Parametric modeling study of the impact of intracellular radionuclide distribution in targeted alpha therapy

Materials & Methods

A- 1 :•→

 1 Impact of geometry and irradiation parameters on nucleus physical dose, according to radionuclide internalization B-1: Tumor Control Probability as a function of activity per cell 1: Univ. Grenoble Alpes, CNRS, Grenoble INP, LPSC-IN2P3, 38000 Grenoble, France 2: IP2I, Université Claude Bernard Lyon 1, CNRS/IN2P3, 69622 Villeurbanne, France 3: Université Clermont Auvergne, CNRS/IN2P3, LPC, 63000 Clermont-Ferrand, France [3] Objectives Intracellular radionuclide distribution scenarios considered in this study • Low impact of cytoplasm only internalization • Moderate impact of nucleus only internalization • High impact of small and low compaction spheroid • Threshold effect around 0.15 mBq per cell • At 0.15 mBq per cell: ~ 18 fold higher TCP between nucleus and membrane source distribution B-2: RBEµ of alpha particles in the condition of an 211 At TAT treatment Conclusions Perspectives Study the impact of intracellular radionuclide distribution on the efficiency of TAT as a function of influence parameters Monte-Carlo simulations of alpha particles in cells, with Geant4 -CPOP • Output: physical doses, entrance and exit kinetic energies for each nucleus traversal of an alpha particle • Cell survival prediction model • Nucleus = sensitive volume Tumor control probability as a function of the activity per cell (mBq). The simulations were performed in a 95µm radius spheroid, with 75% compaction, irradiated by At-211. A-2: Quantification of cross-fire irradiation RBEµ ≃ 6.9 Cross nucleus dose: dose to cell nucleus due to radionuclide not fixed to this cell • In this study ≃ 65 to 98% of total irradiation → Cross-fire effect more important than intracellular distribution due to high range of alpha particles RBEµ: Relative biological effectiveness at the micrometric scale, compared to a reference photon irradiation. High biological impact of alpha particle, confirmed by literature [4]. Observables: Physical dose (also called specific energy, at the microscopic scale), cell survival, tumor control probability (cell line: Human Salivary Gland) Nanodosimetry Microdosimetry • Takes into account variation of damage density with the ion's energy Combined calculations of cell survivals S and TCP : Targeted Alpha Therapy: Vectorization of an α-emitter radionuclide in tumors thanks to targeting pharmaceutical agent Mean α energies : 5-10 MeV Mean path length : 40-100 µm (few cells) • Modeling of intratumoral heterogeneity of radionuclide distribution • Validation against experimental data • Modeling radionuclide diffusion kinetic • Cross-fire effect major in targeted alpha therapy • Intracellular radionuclide distribution must be precisely modeled for small tumors (< 50µm radius), especially with low radionuclide concentration • Biological quantities mandatory to consider, in addition to physical ones irradiated by At-211. In each plot, one parameter was changed at a time. Minimum observed cross-fire nucleus dose %: 30µm radius spheroid RBEµ value found at 10% cell survival, for a membrane source distribution • Output: radiobiological coefficients [2] Agostinelli, Sea, et al. Nucl. Instrum. Methods. Phys. Res. B NUCL INSTRUM METH A506.3 (2003): 250-303.Z [3] Cunha, Micaela, et al. Physics in Medicine & Biology 62.4 (2017): 1248. [1] Maigne, L., et al. Physica Medica 89 (2021): 41-50 Geant4 simulation of an alpha particle crossing a cell nucleus Contact: victor.levrague@lpsc.in2p3.fr Proposed method to predict biological effects: Combination of biophysical modeling and Monte-Carlo simulations at the micrometric scale Heterogeneous dose deposition at the micro-metric scale: Two identical macroscopic doses ≠ two identical biological effects Loucas, Bradford D., et al. Radiation research 179.1 (2013): 9-20.