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

Ines Melo E Costa; George Firth; Jana Kim; Arshiya Banu; Truc Pham; Kavitha Sunassee; Sophie Langdon; Vittorio De Santis; Laurence Vass; Giuseppe Schettino; Gilbert Fruhwirth; Samantha Terry

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

Ines Melo E Costa, George Firth, Jana Kim, Arshiya Banu, Truc Pham, Kavitha Sunassee, Sophie Langdon, Vittorio De Santis, Laurence Vass, Giuseppe Schettino, Gilbert Fruhwirth, Samantha Terry^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

33 Downloads (Pure)

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 language	English
Journal	International Journal of Radiation Oncology Biology Physics
Publication status	Accepted/In press - 17 May 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

Manuscript_final_2Accepted author manuscript, 106 KBLicence: CC BY
Supplementary_Information_final_2Accepted author manuscript, 4.29 MBLicence: CC BY

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this

Melo E Costa, I., Firth, G., Kim, J., Banu, A., Pham, T., Sunassee, K., Langdon, S., De Santis, V., Vass, L., Schettino, G., Fruhwirth, G., & Terry, S. (Accepted/In press). 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. International Journal of Radiation Oncology Biology Physics.

@article{11b77b1073a742d0ae09bfd7c45c8332,

title = "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",

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{\textregistered}. 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.",

author = "{Melo E Costa}, Ines and George Firth and Jana Kim and Arshiya Banu and Truc Pham and Kavitha Sunassee and Sophie Langdon and {De Santis}, Vittorio and Laurence Vass and Giuseppe Schettino and Gilbert Fruhwirth and Samantha Terry",

year = "2024",

month = may,

day = "17",

language = "English",

journal = "International Journal of Radiation Oncology Biology Physics",

issn = "0360-3016",

publisher = "Elsevier",

}

Melo E Costa, I , Firth, G , Kim, J , Banu, A , Pham, T , Sunassee, K , Langdon, S , De Santis, V , Vass, L, Schettino, G, Fruhwirth, G & Terry, S 2024, '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', International Journal of Radiation Oncology Biology Physics.

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. / Melo E Costa, Ines ; Firth, George ; Kim, Jana et al.
In: International Journal of Radiation Oncology Biology Physics, 17.05.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - In vitro and preclinical systematic dose-effect studies of Auger electron- and beta particle-emitting radionuclides and external beam radiation for cancer treatment

T2 - Dose-effect relationship for Auger electrons and beta particles

AU - Melo E Costa, Ines

AU - Firth, George

AU - Kim, Jana

AU - Banu, Arshiya

AU - Pham, Truc

AU - Sunassee, Kavitha

AU - Langdon, Sophie

AU - De Santis, Vittorio

AU - Vass, Laurence

AU - Schettino, Giuseppe

AU - Fruhwirth, Gilbert

AU - Terry, Samantha

PY - 2024/5/17

Y1 - 2024/5/17

N2 - 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.

AB - 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.

M3 - Article

SN - 0360-3016

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

ER -

Melo E Costa I , Firth G , Kim J , Banu A , Pham T , Sunassee K et al. 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. International Journal of Radiation Oncology Biology Physics. 2024 May 17.