目的:尽管放射性药物疗法的临床应用有所增加,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。这里,我们着手定义俄歇电子发射器[99mTc]TcO4和[123I]I的这种关系,和β-粒子发射体[188Re]ReO4。使用允许直接放射性核素比较的基因修饰细胞进行研究。
方法:三阴性MDA-MB-231乳腺癌细胞,表达人钠/碘转运体(hNIS)和绿色荧光蛋白(GFP;MDA-MB-231。使用hNIS-GFP)。使用克隆形成测定法确定[99mTc]TcO4,[123I]I和[188Re]ReO4的体外放射毒性。放射性核素吸收,外排,和亚细胞位置用于使用医学内部辐射剂量形式计算核吸收剂量。使用携带原位MDA-MB-231的雌性NSG小鼠进行体内研究。hNIS-GFP肿瘤,并与X射线处理(12.6-15Gy)和未处理的组群进行比较。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到参考人类成人模型。
结果:[99mTc]TcO4-和[123I]I仅在表达hNIS的细胞中降低了存活率,而[188Re]ReO4降低了表达hNIS和亲本细胞中的存活分数。[123I]与[99mTc]TcO4-和[188Re]ReO4相比,我需要降低2.4倍和1.5倍的衰变/细胞才能达到37%的存活率。孵育72小时后。此外,[99mTc]TcO4-,与X射线相比,[123I]I和[188Re]ReO4在体外具有优越的细胞杀伤效力。在体内,与[188Re]ReO4和[123I]I相比,X射线导致了更高的中位生存期(54天对45天和43天,分别)。与X射线队列不同,在接受放射性核素治疗的队列中未观察到转移.在女性和男性模型中,[188Re]ReO4对1g肿瘤的人吸收剂量比[123I]I高13.8倍和11.2倍,分别。
结论:这项工作报告了使用细胞和肿瘤模型对[99mTc]TcO4,[123I]I,和[188Re]ReO4,第一次。我们进一步证明了[123I]I的肿瘤控制作用,和[188Re]ReO4与EBRT相比。
OBJECTIVE: 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.
METHODS: 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 (MIRD) formalism. In vivo studies were performed using female NSG mice bearing orthotopic MDA-MB-231.hNIS-GFP tumors and compared with X-ray-treated (12.6-15 Gy) and untreated cohorts. Absorbed dose per unit activity in tumors and sodium iodide symporter-expressing organs was extrapolated to reference human adult models using OLINDA/EXM.
RESULTS: [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- and 1.5-fold lower decays/cell to achieve 37% survival compared with [99mTc]TcO4- and [188Re]ReO4-, respectively, after 72 hours of incubation. Additionally, [99mTc]TcO4-, [123I]I-, and [188Re]ReO4- had superior cell killing effectiveness in vitro compared with X-rays. In vivo, X-ray led to a greater median survival compared with [188Re]ReO4- and [123I]I- (54 days vs 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- and 11.2-fold greater than for [123I]I- in female and male models, respectively.
CONCLUSIONS: 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 with external beam radiation therapy.