The Emission of Internal Conversion Electrons Rather Than Auger Electrons Increased the Nucleus-Absorbed Dose for161Tb Compared with177Lu with a Higher Dose Response for 161TbTb-DOTA-LM3 Than for 161TbTb-DOTATATE

Preclinical data have shown that 161Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their 177Lu-labeled counterparts. To further substantiate this enhanced therapeutic effect, we performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose–response curves to evaluate differences in relative biological effectiveness in vitro. Methods: CA20948 cell survival was assessed after treatment with 161TbTb- and 177LuLu-DOTATATE (agonist) and with 161TbTb- and 177LuLu-DOTA-LM3 (antagonist) via a clonogenic assay. Cell binding, internalization, and dissociation assays were performed up to 7 d to acquire time-integrated activity coefficients. Separate S values for each type of particle emission (Auger/internal conversion IC electrons and β− particles) were computed via Monte Carlo simulations, while considering spheric cells. Once the absorbed dose to the cell nucleus was calculated, survival curves were fitted to the appropriate linear or linear-quadratic model and corresponding relative biological effectiveness was evaluated. Results: Although the radiopeptide uptake was independent of the radionuclide, 161TbTb-DOTATATE and 161TbTb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their 177Lu-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of IC and not Auger electrons by 161Tb. When activity concentrations were considered, both 161TbTb-DOTATATE and 161TbTb-DOTA-LM3 showed a lower survival fraction than did labeling with 177Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose–response curves for 161TbTb- and 177LuLu-DOTATATE. 161TbTb-DOTA-LM3 showed a linear-quadratic dose response, whereas 161TbTb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. Conclusion: The IC, rather than Auger, electrons emitted by 161Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for 161TbTb-DOTATATE and 161TbTb-DOTA-LM3 than for the 177Lu-labeled analogs. In contrast, 161TbTb-DOTATATE showed no higher dose response than 177LuLu-DOTATATE, whereas for 161TbTb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, 161TbTb-DOTA-LM3 is a more effective radiopeptide than 161TbTb-DOTATATE for labeling with 161Tb.