The Emission of Internal Conversion Electrons Rather Than Auger Electrons Increased the Nucleus-Absorbed Dose for Tb Compared with Lu with a Higher Dose Response for [Tb]Tb-DOTA-LM3 Than for [Tb]Tb-DOTATATE.

Preclinical data have shown that Tb-labeled peptides targeting the somatostatin receptor are therapeutically more effective for peptide receptor radionuclide therapy than are their Lu-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. CA20948 cell survival was assessed after treatment with [Tb]Tb- and [Lu]Lu-DOTATATE (agonist) and with [Tb]Tb- and [Lu]Lu-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 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. Although the radiopeptide uptake was independent of the radionuclide, [Tb]Tb-DOTATATE and [Tb]Tb-DOTA-LM3 delivered a 3.6 and 3.8 times higher dose to the nucleus, respectively, than their Lu-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 Tb. When activity concentrations were considered, both [Tb]Tb-DOTATATE and [Tb]Tb-DOTA-LM3 showed a lower survival fraction than did labeling with Lu. When the absorbed dose to the nucleus was considered, no significant difference could be observed between the dose-response curves for [Tb]Tb- and [Lu]Lu-DOTATATE. [Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [Tb]Tb-DOTATATE showed only a linear dose response within the observed dose range, suggesting additional cell membrane damage by Auger electrons. The IC, rather than Auger, electrons emitted by Tb resulted in a higher absorbed dose to the cell nucleus and lower clonogenic survival for [Tb]Tb-DOTATATE and [Tb]Tb-DOTA-LM3 than for the Lu-labeled analogs. In contrast, [Tb]Tb-DOTATATE showed no higher dose response than [Lu]Lu-DOTATATE, whereas for [Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [Tb]Tb-DOTATATE for labeling with Tb.