In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment

Ines M Costa; George Firth; Jana Kim; Arshiya Banu; Truc T Pham; Kavitha Sunassee; Sophie Langdon; Vittorio De Santis; Laurence Vass; Giuseppe Schettino; Gilbert O Fruhwirth; Samantha Y A Terry

doi:10.1016/j.ijrobp.2024.05.017

In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment

Ines M Costa, George Firth, Jana Kim, Arshiya Banu, Truc T Pham, Kavitha Sunassee, Sophie Langdon, Vittorio De Santis, Laurence Vass, Giuseppe Schettino, Gilbert O Fruhwirth, Samantha Y A Terry

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

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]TcO 4 - and [ 123I]I - and β - -particle emitter [ 188Re]ReO 4 -. 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - 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]TcO 4 - and [ 123I]I - reduced the survival fraction only in hNIS-expressing cells, whereas [ 188Re]ReO 4 - 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]TcO 4 - and [ 188Re]ReO 4 -, respectively, after 72 hours of incubation. Additionally, [ 99mTc]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - had superior cell killing effectiveness in vitro compared with X-rays. In vivo, X-ray led to a greater median survival compared with [ 188Re]ReO 4 - 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]ReO 4 - 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - for the first time. We further demonstrate the tumor-controlling effects of [ 123I]I - and [ 188Re]ReO 4 - in comparison with external beam radiation therapy.

Original language	English
Journal	International journal of radiation oncology, biology, physics
DOIs	https://doi.org/10.1016/j.ijrobp.2024.05.017
Publication status	E-pub ahead of print - 24 May 2024

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10.1016/j.ijrobp.2024.05.017

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Costa, I. M., Firth, G., Kim, J., Banu, A., Pham, T. T., Sunassee, K., Langdon, S., De Santis, V., Vass, L., Schettino, G., Fruhwirth, G. O., & Terry, S. Y. A. (2024). In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment. International journal of radiation oncology, biology, physics. Advance online publication. https://doi.org/10.1016/j.ijrobp.2024.05.017

@article{be63f51efd6f4ca6aecee190f6c933d9,

title = "In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment",

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]TcO 4 - and [ 123I]I - and β - -particle emitter [ 188Re]ReO 4 -. 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - 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]TcO 4 - and [ 123I]I - reduced the survival fraction only in hNIS-expressing cells, whereas [ 188Re]ReO 4 - 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]TcO 4 - and [ 188Re]ReO 4 -, respectively, after 72 hours of incubation. Additionally, [ 99mTc]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - had superior cell killing effectiveness in vitro compared with X-rays. In vivo, X-ray led to a greater median survival compared with [ 188Re]ReO 4 - 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]ReO 4 - 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - for the first time. We further demonstrate the tumor-controlling effects of [ 123I]I - and [ 188Re]ReO 4 - in comparison with external beam radiation therapy. ",

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

year = "2024",

month = may,

day = "24",

doi = "10.1016/j.ijrobp.2024.05.017",

language = "English",

journal = "International journal of radiation oncology, biology, physics",

issn = "0360-3016",

publisher = "Elsevier",

}

Costa, IM, Firth, G , Kim, J , Banu, A , Pham, TT , Sunassee, K , Langdon, S , De Santis, V , Vass, L, Schettino, G, Fruhwirth, GO & Terry, SYA 2024, 'In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment', International journal of radiation oncology, biology, physics. https://doi.org/10.1016/j.ijrobp.2024.05.017

TY - JOUR

T1 - In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment

AU - Costa, Ines M

AU - Firth, George

AU - Kim, Jana

AU - Banu, Arshiya

AU - Pham, Truc T

AU - Sunassee, Kavitha

AU - Langdon, Sophie

AU - De Santis, Vittorio

AU - Vass, Laurence

AU - Schettino, Giuseppe

AU - Fruhwirth, Gilbert O

AU - Terry, Samantha Y A

PY - 2024/5/24

Y1 - 2024/5/24

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]TcO 4 - and [ 123I]I - and β - -particle emitter [ 188Re]ReO 4 -. 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - 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]TcO 4 - and [ 123I]I - reduced the survival fraction only in hNIS-expressing cells, whereas [ 188Re]ReO 4 - 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]TcO 4 - and [ 188Re]ReO 4 -, respectively, after 72 hours of incubation. Additionally, [ 99mTc]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - had superior cell killing effectiveness in vitro compared with X-rays. In vivo, X-ray led to a greater median survival compared with [ 188Re]ReO 4 - 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]ReO 4 - 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - for the first time. We further demonstrate the tumor-controlling effects of [ 123I]I - and [ 188Re]ReO 4 - in comparison with external beam radiation therapy.

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]TcO 4 - and [ 123I]I - and β - -particle emitter [ 188Re]ReO 4 -. 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - 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]TcO 4 - and [ 123I]I - reduced the survival fraction only in hNIS-expressing cells, whereas [ 188Re]ReO 4 - 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]TcO 4 - and [ 188Re]ReO 4 -, respectively, after 72 hours of incubation. Additionally, [ 99mTc]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - had superior cell killing effectiveness in vitro compared with X-rays. In vivo, X-ray led to a greater median survival compared with [ 188Re]ReO 4 - 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]ReO 4 - 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]TcO 4 -, [ 123I]I -, and [ 188Re]ReO 4 - for the first time. We further demonstrate the tumor-controlling effects of [ 123I]I - and [ 188Re]ReO 4 - in comparison with external beam radiation therapy.

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U2 - 10.1016/j.ijrobp.2024.05.017

DO - 10.1016/j.ijrobp.2024.05.017

M3 - Article

C2 - 38797497

SN - 0360-3016

JO - International journal of radiation oncology, biology, physics

JF - International journal of radiation oncology, biology, physics

ER -

In Vitro and Preclinical Systematic Dose-Effect Studies of Auger Electron- and β Particle-Emitting Radionuclides and External Beam Radiation for Cancer Treatment

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