尽管放射性药物疗法的临床使用有所增加，但人们对放射性核素的生物学效应及其与吸收辐射剂量的关系知之甚少。在这里，我们着手定义俄歇电子发射体 [99mTc]TcO4 和 [123I]I 以及 β-粒子发射体 [188Re]ReO4 的这种关系。研究使用允许直接放射性核素比较的转基因细胞进行。三阴性 MDA-MB-231 乳腺癌细胞，表达人类钠/碘同向转运蛋白 (hNIS) 和绿色荧光蛋白 (GFP; MDA-MB-231.使用hNIS-GFP)。 [99mTc]TcO4、[123I]I 和 [188Re]ReO4 的体外放射毒性通过克隆形成试验测定。放射性核素吸收、流出和亚细胞定位用于使用医学内辐射剂量形式计算核吸收剂量。使用携带原位 MDA-MB-231.hNIS-GFP 肿瘤的雌性 NSG 小鼠进行体内研究，并与 X 射线治疗（12.6-15 Gy）和未治疗组进行比较。使用 OLINDA/EXM® 将肿瘤和 NIS 表达器官中每单位活性的吸收剂量外推至参考人类成人模型。[99mTc]TcO4- 和 [123I]I 仅降低 hNIS 表达细胞的存活分数，而 [188Re] ReO4 降低了表达 hNIS 的细胞和亲本细胞的存活率。孵育 72 小时后，与 [99mTc]TcO4- 和 [188Re]ReO4 相比，[123I]I 需要分别降低 2.4 倍和 1.5 倍/细胞的衰变才能实现 37% 的存活率。此外，与X射线相比，[99mTc]TcO4-、[123I]I和[188Re]ReO4在体外具有优异的细胞杀伤效果。在体内，与 [188Re]ReO4 和 [123I]I 相比，X 射线导致更高的中位生存期（分别为 54 天、45 天和 43 天）。与 X 射线队列不同，在放射性核素治疗组中未观察到转移。外推人体对 1 g 肿瘤吸收的 [188Re]ReO4 剂量分别比女性和男性模型中 [123I]I 的吸收剂量高 13.8 倍和 11.2 倍。这项工作报告了使用细胞和肿瘤模型的参考剂量效应数据首次获得[99mTc]TcO4、[123I]I和[188Re]ReO4。我们进一步证明了 [123I]I 和 [188Re]ReO4 与 EBRT 相比的肿瘤控制作用。版权所有 © 2024。由 Elsevier Inc. 出版。

Despite a rise in clinical use of radiopharmaceutical therapies, the biological effects of radionuclides and their relationship with absorbed radiation dose are poorly understood. Here, we set out to define this relationship for Auger electron-emitters [99mTc]TcO4 and [123I]I, and β--particle-emitter [188Re]ReO4. Studies were carried out using genetically-modified cells that permitted direct radionuclide comparisons.Triple-negative MDA-MB-231 breast cancer cells, expressing the human sodium/iodide symporter (hNIS) and green fluorescent protein (GFP; MDA-MB-231.hNIS-GFP) were used. In vitro radiotoxicity of [99mTc]TcO4, [123I]I and [188Re]ReO4 was determined using clonogenic assays. Radionuclide uptake, efflux, and subcellular location were used to calculate nuclear-absorbed doses using the Medical Internal Radiation Dose formalism. In vivo studies were performed using female NSG mice bearing orthotopic MDA-MB-231.hNIS-GFP tumors and compared to X-ray-treated (12.6-15 Gy) and untreated cohorts. Absorbed dose per unit activity in tumors and NIS-expressing organs were extrapolated to reference human adult models using OLINDA/EXM®.[99mTc]TcO4- and [123I]I reduced the survival fraction only in hNIS-expressing cells, whereas [188Re]ReO4 reduced survival fraction in hNIS-expressing and parental cells. [123I]I required 2.4-fold and 1.5-fold lower decays/cell to achieve 37% survival compared to [99mTc]TcO4- and [188Re]ReO4, respectively, following 72 hours incubation. Additionally, [99mTc]TcO4-, [123I]I and [188Re]ReO4 had superior cell killing effectiveness in vitro compared to X-rays. In vivo, X-ray led to a greater median survival compared to [188Re]ReO4 and [123I]I (54 days versus 45 and 43 days, respectively). Unlike the X-ray cohort, no metastases were visualized in the radionuclide-treated cohorts. Extrapolated human absorbed doses of [188Re]ReO4 to a 1 g tumor were 13.8-fold and 11.2-fold greater than for [123I]I in female and male models, respectively.This work reports reference dose-effect data using cell and tumor models for [99mTc]TcO4, [123I]I, and [188Re]ReO4, for the first time. We further demonstrate the tumor controlling effects of [123I]I, and [188Re]ReO4 in comparison to EBRT.Copyright © 2024. Published by Elsevier Inc.