TY - JOUR
T1 - A reactivity-based 18F-labeled probe for PET imaging of oxidative stress in chemotherapy-induced cardiotoxicity
AU - Mota, Filipa
AU - Pell, Victoria
AU - Singh, Nisha
AU - Baark, Fred
AU - Waters, Ed
AU - Sadasivam, Pragalath
AU - Southworth, Richard
AU - Yan, Ran
N1 - Funding Information:
F.M. would like to thank the British Heart Foundation [PG/15/60/31629] for supporting this work. F.B. and V.P. thank the BHF project grant [PG/16/43/32141]. E.W. thanks the EPSRC Ph.D. studentship [EP/M506357/1]. This work was supported by the Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z]. The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The Comprehensive Cancer Imaging Centre of King’s College London and UCL was funded by the CRUK and EPSRC in association with the MRC and DoH (England). This work was supported by a Wellcome Trust Multi-User Equipment grant [212885/Z/18Z]. This work was supported by EPSRC Program grants [EP/S019901/1 and EP/S032789/1]. The authors would like to thank the radiochemists at St. Thomas Hospital PET Centre for proving F-fluoride and Kavitha Sunnassee and Jayanta K. Bordoloi for their assistance with the in vivo protocols and operation of the PET scanners. 18
Funding Information:
F.M. would like to thank the British Heart Foundation [PG/15/60/31629] for supporting this work. F.B. and V.P. thank the BHF project grant [PG/16/43/32141]. E.W. thanks the EPSRC Ph.D. studentship [EP/M506357/1]. This work was supported by the Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z]. The research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at Guy?s and St Thomas? NHS Foundation Trust and King?s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. The Comprehensive Cancer Imaging Centre of King?s College London and UCL was funded by the CRUK and EPSRC in association with the MRC and DoH (England). This work was supported by a Wellcome Trust Multi-User Equipment grant [212885/Z/18Z]. This work was supported by EPSRC Program grants [EP/S019901/1 and EP/S032789/1]. The authors would like to thank the radiochemists at St. Thomas Hospital PET Centre for proving 18F-fluoride and Kavitha Sunnassee and Jayanta K. Bordoloi for their assistance with the in vivo protocols and operation of the PET scanners.
Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2022/1/3
Y1 - 2022/1/3
N2 - Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.
AB - Oxidative stress underlies the pathology of many human diseases, including the doxorubicin-induced off-target cardiotoxicity in cancer chemotherapies. Since current diagnostic procedures are only capable of monitoring cardiac function, a noninvasive means of detecting biochemical changes in redox status prior to irreversible functional changes is highly desirable for both early diagnosis and prognosis. We designed a novel 18F-labeled molecular probe, 18F-FPBT, for the direct detection of superoxide in vivo using positron emission tomography (PET). 18F-FPBT was radiosynthesized in one step by nucleophilic radiofluorination. In vitro, 18F-FPBT showed rapid and selective oxidation by superoxide (around 60% in 5 min) compared to other physiological ROS. In healthy mice and rats, 18F-FBPT is distributed to all major organs in the first few minutes post injection and is rapidly cleared via both renal and hepatobiliary routes with minimal background retention in the heart. In a rat model of doxorubicin-induced cardiotoxicity, 18F-FBPT showed significantly higher (P < 0.05) uptake in the hearts of treated animals compared to healthy controls. These results warrant further optimization of 18F-FBPT for clinical translation.
KW - reactive oxygen species, oxidative stress, cardiotoxicity, PET imaging, fluorine-18
UR - http://www.scopus.com/inward/record.url?scp=85120891473&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.1c00496
DO - 10.1021/acs.molpharmaceut.1c00496
M3 - Article
SN - 1543-8384
VL - 19
SP - 18
EP - 25
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 1
ER -
