Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells

Emily Russell; Victoria Dunne; Ben Russell; Hibaaq Mohamud; Mihaela Ghita; Stephen J. McMahon; Karl T. Butterworth; Giuseppe Schettino; Conor K. McGarry; Kevin M. Prise

doi:10.1186/s13014-021-01829-y

Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells

Emily Russell^*, Victoria Dunne, Ben Russell, Hibaaq Mohamud, Mihaela Ghita, Stephen J. McMahon, Karl T. Butterworth, Giuseppe Schettino, Conor K. McGarry, Kevin M. Prise

^*Corresponding author for this work

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

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Abstract

PURPOSE: The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model.

METHODS: SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs.

RESULTS: The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 μg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05).

CONCLUSIONS: SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

Original language	English
Article number	104
Journal	Radiation oncology (London, England)
Volume	16
DOIs	https://doi.org/10.1186/s13014-021-01829-y
Publication status	Published - 12 Jun 2021

Bibliographical note

Funding Information:
This work is a collaboration between Queen’s University Belfast, and the National Physical Laboratory, funded by the Medical Research Council (Ref: MR/P01593X/1).

Funding Information:
This work is a collaboration between Queen’s University Belfast, and the National Physical Laboratory, funded by the Medical Research Council (Ref: MR/P01593X/1). V. Dunne was supported by the LFT Charitable Trust and M. Ghita by the Tom Simms Memorial Fund. Thanks is given to Dr Jascindra Ravi of the Bio-metrology group at the National Physical Laboratory.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Keywords

Nanoparticles
Radiobiology

ASJC Scopus subject areas

Oncology
Radiology Nuclear Medicine and imaging

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10.1186/s13014-021-01829-yLicence: CC BY

Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells
Copyright 2021 the authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 1.83 MBLicence: CC BY

Cite this

@article{6ffc83980d6e4a85b937aeb49e2095a0,

title = "Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells",

abstract = "PURPOSE: The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model.METHODS: SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs.RESULTS: The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 μg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05).CONCLUSIONS: SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.",

keywords = "Nanoparticles, Radiobiology",

author = "Emily Russell and Victoria Dunne and Ben Russell and Hibaaq Mohamud and Mihaela Ghita and McMahon, {Stephen J.} and Butterworth, {Karl T.} and Giuseppe Schettino and McGarry, {Conor K.} and Prise, {Kevin M.}",

note = "Funding Information: This work is a collaboration between Queen{\textquoteright}s University Belfast, and the National Physical Laboratory, funded by the Medical Research Council (Ref: MR/P01593X/1). Funding Information: This work is a collaboration between Queen{\textquoteright}s University Belfast, and the National Physical Laboratory, funded by the Medical Research Council (Ref: MR/P01593X/1). V. Dunne was supported by the LFT Charitable Trust and M. Ghita by the Tom Simms Memorial Fund. Thanks is given to Dr Jascindra Ravi of the Bio-metrology group at the National Physical Laboratory. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = jun,

day = "12",

doi = "10.1186/s13014-021-01829-y",

language = "English",

volume = "16",

journal = "Radiation Oncology",

issn = "1748-717X",

publisher = "BioMed Central",

}

TY - JOUR

T1 - Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells

AU - Russell, Emily

AU - Dunne, Victoria

AU - Russell, Ben

AU - Mohamud, Hibaaq

AU - Ghita, Mihaela

AU - McMahon, Stephen J.

AU - Butterworth, Karl T.

AU - Schettino, Giuseppe

AU - McGarry, Conor K.

AU - Prise, Kevin M.

N1 - Funding Information: This work is a collaboration between Queen’s University Belfast, and the National Physical Laboratory, funded by the Medical Research Council (Ref: MR/P01593X/1). Funding Information: This work is a collaboration between Queen’s University Belfast, and the National Physical Laboratory, funded by the Medical Research Council (Ref: MR/P01593X/1). V. Dunne was supported by the LFT Charitable Trust and M. Ghita by the Tom Simms Memorial Fund. Thanks is given to Dr Jascindra Ravi of the Bio-metrology group at the National Physical Laboratory. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6/12

Y1 - 2021/6/12

N2 - PURPOSE: The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model.METHODS: SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs.RESULTS: The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 μg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05).CONCLUSIONS: SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

AB - PURPOSE: The recent implementation of MR-Linacs has highlighted theranostic opportunities of contrast agents in both imaging and radiotherapy. There is a lack of data exploring the potential of superparamagnetic iron oxide nanoparticles (SPIONs) as radiosensitisers. Through preclinical 225 kVp exposures, this study aimed to characterise the uptake and radiobiological effects of SPIONs in tumour cell models in vitro and to provide proof-of-principle application in a xenograft tumour model.METHODS: SPIONs were also characterised to determine their hydrodynamic radius using dynamic light scattering and uptake was measured using ICP-MS in 6 cancer cell lines; H460, MiaPaCa2, DU145, MCF7, U87 and HEPG2. The impact of SPIONs on radiobiological response was determined by measuring DNA damage using 53BP1 immunofluorescence and cell survival. Sensitisation Enhancement Ratios (SERs) were compared with the predicted Dose Enhancement Ratios (DEFs) based on physical absorption estimations. In vivo efficacy was demonstrated using a subcutaneous H460 xenograft tumour model in SCID mice by following intra-tumoural injection of SPIONs.RESULTS: The hydrodynamic radius was found to be between 110 and 130 nm, with evidence of being monodisperse in nature. SPIONs significantly increased DNA damage in all cell lines with the exception of U87 cells at a dose of 1 Gy, 1 h post-irradiation. Levels of DNA damage correlated with the cell survival, in which all cell lines except U87 cells showed an increased sensitivity (P < 0.05) in the linear quadratic curve fit for 1 h exposure to 23.5 μg/ml SPIONs. There was also a 30.1% increase in the number of DNA damage foci found for HEPG2 cells at 2 Gy. No strong correlation was found between SPION uptake and DNA damage at any dose, yet the biological consequences of SPIONs on radiosensitisation were found to be much greater, with SERs up to 1.28 ± 0.03, compared with predicted physical dose enhancement levels of 1.0001. In vivo, intra-tumoural injection of SPIONs combined with radiation showed significant tumour growth delay compared to animals treated with radiation or SPIONs alone (P < 0.05).CONCLUSIONS: SPIONs showed radiosensitising effects in 5 out of 6 cancer cell lines. No correlation was found between the cell-specific uptake of SPIONs into the cells and DNA damage levels. The in vivo study found a significant decrease in the tumour growth rate.

KW - Nanoparticles

KW - Radiobiology

U2 - 10.1186/s13014-021-01829-y

DO - 10.1186/s13014-021-01829-y

M3 - Article

C2 - 34118963

VL - 16

JO - Radiation Oncology

JF - Radiation Oncology

SN - 1748-717X

M1 - 104

ER -

Impact of superparamagnetic iron oxide nanoparticles on in vitro and in vivo radiosensitisation of cancer cells

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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