In vitro and preclinical systematic dose-effect studies of Auger electron- and beta particle-emitting radionuclides and external beam radiation for cancer treatment: Dose-effect relationship for Auger electrons and beta particles

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Abstract

Purpose. 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 and Materials. 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®. 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-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. 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 to EBRT.
Original languageEnglish
JournalInternational Journal of Radiation Oncology Biology Physics
Publication statusAccepted/In press - 17 May 2024

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