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 [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE (agonist) and with [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]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 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, [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-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 [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-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 [¹⁶¹Tb]Tb- and [¹⁷⁷Lu]Lu-DOTATATE. [¹⁶¹Tb]Tb-DOTA-LM3 showed a linear-quadratic dose response, whereas [¹⁶¹Tb]Tb-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 [¹⁶¹Tb]Tb-DOTATATE and [¹⁶¹Tb]Tb-DOTA-LM3 than for the ¹⁷⁷Lu-labeled analogs. In contrast, [¹⁶¹Tb]Tb-DOTATATE showed no higher dose response than [¹⁷⁷Lu]Lu-DOTATATE, whereas for [¹⁶¹Tb]Tb-DOTA-LM3 an additional quadratic response was observed. Because of this quadratic response, potentially caused by cell membrane damage, [¹⁶¹Tb]Tb-DOTA-LM3 is a more effective radiopeptide than [¹⁶¹Tb]Tb-DOTATATE for labeling with ¹⁶¹Tb.

临床前数据表明，靶向生长抑素受体的 ¹⁶¹个 Tb 标记肽对肽受体放射性核素治疗比其 ¹⁷⁷个 Lu 标记的对应肽在治疗上更有效。为了进一步证实这种增强的治疗效果，我们进行了细胞剂量测定以量化细胞核的吸收剂量，并比较剂量-反应曲线以评估体外相对生物学有效性的差异。方法：用 [¹⁶¹Tb] Tb- 和 [¹⁷⁷Lu]Lu-DOTALATE （激动剂） 以及 [¹⁶¹Tb] Tb- 和 [¹⁷⁷Lu] Lu-DOTA-LM3 （拮抗剂） 处理后，通过克隆形成测定评估CA20948细胞存活率。进行细胞结合、内化和解离测定长达 7 天，以获得时间积分活性系数。在考虑球形单元的同时，通过蒙特卡洛模拟计算每种粒子发射类型（俄歇/内转换 [IC] 电子和 β^– 粒子）的单独 S 值。一旦计算出细胞核的吸收剂量，将生存曲线拟合到适当的线性或线性-二次模型，并评估相应的相对生物学有效性。结果：尽管放射性肽摄取与放射性核素无关，但 [¹⁶¹Tb]Tb-DOTATATE 和 [¹⁶¹Tb]Tb-DOTA-LM3 向细胞核输送的剂量分别比它们的 ¹⁷⁷个 Lu 标记的饱和受体结合对应物高 3.6 倍和 3.8 倍。这种增加的原子核吸收剂量主要是由于 IC 而不是俄歇电子的额外发射 ¹⁶¹Tb。 当考虑活性浓度时，[¹⁶¹Tb]Tb-DOTATATE 和 [¹⁶¹Tb]Tb-DOTA-LM3 的存活分数均低于 ¹⁷⁷Lu 标记。当考虑对细胞核的吸收剂量时，在 [¹⁶¹Tb]Tb 和 [¹⁷⁷Lu]Lu-DOTATATE 的剂量-反应曲线之间没有观察到显着差异。[¹⁶¹结核病]Tb-DOTA-LM3 显示线性二次剂量反应，而 [¹⁶¹Tb]Tb-DOTATATE 在观察到的剂量范围内仅显示线性剂量反应，表明俄歇电子对细胞膜的额外损伤。结论：与 ¹⁷⁷Lu 标记的类似物相比，¹⁶¹Tb 发射的 IC 而不是俄歇电子导致 [¹⁶¹Tb]Tb-DOTATATE 和 [¹⁶¹Tb]Tb-DOTA-LM3 对细胞核的吸收剂量更高，克隆形成存活率更低。相比之下，[¹⁶¹Tb]Tb-DOTATATE 没有显示出比 [¹⁷⁷Lu]Lu-DOTATATE 更高的剂量反应，而对于 [¹⁶¹Tb]Tb-DOTA-LM3，观察到额外的二次反应。由于这种可能由细胞膜损伤引起的二次反应，[¹⁶¹Tb]Tb-DOTA-LM3 是比 [¹⁶¹Tb]Tb-DOTATATE 更有效的放射性肽，用于 ¹⁶¹Tb 标记。