Cellular dosimetry of [177Lu]Lu-DOTA-[Tyr3]octreotate radionuclide therapy: the impact of modeling assumptions on the correlation with in vitro cytotoxicity

Abstract

Background: Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. Therefore, we have built a refined cellular dosimetry model for [ 177 Lu]Lu-DOTA-[Tyr 3 ]octreotate (177 Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. Methods: Time activity curves were measured and modeled for medium, membrane-bound, and internalized activity fractions over 6 days. Clonogenic survival assays were performed at various added activities (0.1-2.5 MBq/ml). 3D microscopy images (stained for cytoplasm, nucleus, and Golgi) were used as reference for developing polygonal meshes (PM) in 3DsMax to accurately render the cellular and organelle geometry. Absorbed doses to the nucleus per decay (S values) were calculated for 3 cellular morphologies: spheres (MIRDcell), truncated cone-shaped constructive solid geometry (CSG within MCNP6.1), and realistic PM models, using Geant4-10.03. The geometrical setup of the clonogenic survival assays was modeled, including dynamic changes in proliferation, proximity variations, and cell death. The absorbed dose to the nucleus by the radioactive source cell (self-dose) and surrounding source cells (cross-dose) was calculated applying the MIRD formalism. Finally, the correlation between absorbed dose and survival fraction was fitted using a linear dose-response curve (high α/β or fast sub-lethal damage repair half-life) for different assumptions, related to cellular shape and localization of the internalized fraction of activity. Results: The cross-dose, depending on cell proximity and colony formation, is a minor (15%) contributor to the total absorbed dose. Cellular volume (inverse exponential trend), shape modeling (up to 65%), and internalized source localization (up to + 149% comparing cytoplasm to Golgi) significantly influence the self-dose to nucleus. The absorbed dose delivered to the nucleus during a clonogenic survival assay is 3-fold higher with MIRDcell compared to the polygonal mesh structures. Our cellular dosimetry model indicates that 177 Lu-DOTATATE treatment might be more effective than suggested by average spherical cell dosimetry, predicting a lower absorbed dose for the same cellular survival. Dose-rate effects and heterogeneous dose delivery might account for differences in dose-response compared to x-ray irradiation.

Modeling early radiation DNA damage occurring during [177Lu]Lu-DOTA-[Tyr3]octreotate radionuclide therapy

“…Indeed, the 177 Lu -cross dose (i.e. the absorbed dose delivered by surrounding cells to a target cell) decreases exponentially with distance and hence increasing the planar cellular cluster size with additional cell layers after a given value (on average 3-4 cell layers) would not significantly contribute to the total absorbed dose received by the nucleus of the central cell (13). The computational memory consumption was drastically reduced by the Geant4 parameterization process, since the tessellated geometries (i.e.…”

“…As a consequence, cell morphology and cell population are not modeled in this scenario. On the contrary, longer-range radionuclides, such as 177 Lu, require a detailed cell morphology and population modeling to account for both self- and cross-irradiation in a planar cell colony ( 13 ). Furthermore, once the irradiation field has been characterized, an event-by-event description of the radiation track structure at the nanometer level within the nucleus, combined with a simulation including a description of the target at the relevant scale (e.g., atom, molecule), needs to be adopted in order to yield conclusions on the biophysical mechanisms involved.…”

Radiation doses from 161Tb and 177Lu in single tumour cells and micrometastases

“…For example, in the work by Goddu et al [34], the spherical cells have a diameter of 10 μm and contain a concentric spherical nucleus of 8 μm diameter, which results in a V nucleus /V cell of ∼ 50%. In the recent study by Tamborino et al [35] with experiments performed on human osteosarcoma cells, the V nucleus /V cell was estimated as ∼ 30% based on 4Pi confocal microscopy.…”

EANM position paper on the role of radiobiology in nuclear medicine

“…This additional input is presently, however, very rarely used, as only limited studies related to therapeutic use of radiopharmaceuticals and including radiobiological parameters are available. Of note, the precision dosimetry approach to describe the dose on the cellular and subcellular level in targeted radionuclide therapy is under development [ 56 , 57 ].…”