Abstract
BackgroundSurvival 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 [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions.MethodsTime 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 set-up 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.ResultsThe 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 177Lu-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.ConclusionOur results demonstrate that modeling of cellular and organelle geometry is crucial to perform accurate in vitro dosimetry.
Highlights
Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry
Our results demonstrate that modeling of cellular and organelle geometry is crucial to perform accurate in vitro dosimetry
Parameter analysis Simplified cellular shapes (MIRDcell) result in higher self S values than PM geometry In previous studies, simplified geometries reproducing cellular morphologies were compared to analyze the impact of shape-modeling on the S values; we have further explored this comparison including, as reference, the reconstruction of 9 confocal microscope images of U2OS+somatostatin receptor type 2 (SST2) cells with voxels and polygonal meshes
Summary
Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. We have built a refined cellular dosimetry model for [177Lu]LuDOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. Targeted radionuclide therapy (TRT) is a promising treatment for solid tumors and micro metastases [1]. Patients with metastasized neuroendocrine tumors (NETs) overexpressing the somatostatin receptor type 2 (SST2) can be treated with peptide receptor radionuclide therapy (PRRT). The fundamental knowledge derived from a better understanding of the action of ionizing radiation on biological matter through the development of cellular dosimetry may provide novel and more effective strategies for TRT treatment delivery. Biological effects from in vitro experiments are mainly reported in direct correlation with the added activities (in MBq/ml), hindering the prediction and comparison of therapeutic efficacy of different radiopharmaceuticals
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