Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy

Cinzia Imberti; Jamie Lok; James P.C. Coverdale; Oliver W. L. Carter; Millie E. Fry; Miles L. Postings; Jana Kim; George Firth; Philip J. Blower; Peter J. Sadler

doi:10.1021/acs.inorgchem.3c02245

Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy

Cinzia Imberti^*, Jamie Lok, James P.C. Coverdale, Oliver W. L. Carter, Millie E. Fry, Miles L. Postings, Jana Kim, George Firth, Philip J. Blower, Peter J. Sadler^*

^*Corresponding author for this work

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Abstract

A novel photoactivatable Pt(IV) diazido anticancer agent, Pt-succ-DFO, bearing a pendant deferoxamine (DFO) siderophore for radiometal chelation, has been synthesized for the study of its in vivo behavior with radionuclide imaging. Pt-succ-DFO complexation of Fe(III) and Ga(III) ions yielded new heterobimetallic complexes that maintain the photoactivation properties and photocytotoxicity of the parent Pt complex in human cancer cell lines. Radiolabeled Pt-succ-DFO-⁶⁸Ga (t_1/2 = 68 min, positron emitter) was readily prepared under mild conditions and was stable in the dark upon incubation with human serum. PET imaging of Pt-succ-DFO-⁶⁸Ga in healthy mice revealed a promising biodistribution profile with rapid renal excretion and limited organ accumulation, implying that little off-target uptake is expected for this class of agents. Overall, this research provides the first in vivo imaging study of the whole-body distribution of a photoactivatable Pt(IV) azido anticancer complex and illustrates the potential of radionuclide imaging as a tool for the preclinical development of novel light-activated agents.

Original language	English
Pages (from-to)	20745-20753
Number of pages	9
Journal	Inorganic Chemistry
Volume	62
Issue number	50
Early online date	29 Aug 2023
DOIs	https://doi.org/10.1021/acs.inorgchem.3c02245
Publication status	Published - 18 Dec 2023

Bibliographical note

Funding Information:
This research was funded by the Wellcome Trust (grant no. 209173/Z/17/Z for C.I.), the Engineering and Physical Sciences Research Council (EPSRC grant no. EP/P030572/1), the Royal Society of Chemistry (grant no. E22-1637945680 for J.P.C.C.), the Wellcome Multiuser Equipment Radioanalytical Facility funded by Wellcome Trust (212885/Z/18/Z), the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S019901/1, “MITHRAS”), GoldenKeys High-tech Materials Co., Ltd., and Anglo-American Platinum. The PET scanner was funded by Wellcome Trust grant 08452/Z/07/Z. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. We thank Lijiang Song and Ivan Prokes for assistance with mass spectrometry and NMR, respectively.

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Inorganic Chemistry

UN SDGs

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

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10.1021/acs.inorgchem.3c02245Licence: Creative Commons: Attribution (CC BY)

ImbertiC2023RadiometalFinal published version, 2.81 MBLicence: Creative Commons: Attribution (CC BY)

Mitochondrial-targeting organometallic catalysts in cancer cells
Coverdale, J.
THE ROYAL SOCIETY OF CHEMISTRY
1/09/22 → 31/08/23
Project: Research

Cite this

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title = "Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy",

abstract = "A novel photoactivatable Pt(IV) diazido anticancer agent, Pt-succ-DFO, bearing a pendant deferoxamine (DFO) siderophore for radiometal chelation, has been synthesized for the study of its in vivo behavior with radionuclide imaging. Pt-succ-DFO complexation of Fe(III) and Ga(III) ions yielded new heterobimetallic complexes that maintain the photoactivation properties and photocytotoxicity of the parent Pt complex in human cancer cell lines. Radiolabeled Pt-succ-DFO-68Ga (t1/2 = 68 min, positron emitter) was readily prepared under mild conditions and was stable in the dark upon incubation with human serum. PET imaging of Pt-succ-DFO-68Ga in healthy mice revealed a promising biodistribution profile with rapid renal excretion and limited organ accumulation, implying that little off-target uptake is expected for this class of agents. Overall, this research provides the first in vivo imaging study of the whole-body distribution of a photoactivatable Pt(IV) azido anticancer complex and illustrates the potential of radionuclide imaging as a tool for the preclinical development of novel light-activated agents.",

author = "Cinzia Imberti and Jamie Lok and Coverdale, {James P.C.} and Carter, {Oliver W. L.} and Fry, {Millie E.} and Postings, {Miles L.} and Jana Kim and George Firth and Blower, {Philip J.} and Sadler, {Peter J.}",

note = "Funding Information: This research was funded by the Wellcome Trust (grant no. 209173/Z/17/Z for C.I.), the Engineering and Physical Sciences Research Council (EPSRC grant no. EP/P030572/1), the Royal Society of Chemistry (grant no. E22-1637945680 for J.P.C.C.), the Wellcome Multiuser Equipment Radioanalytical Facility funded by Wellcome Trust (212885/Z/18/Z), the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S019901/1, “MITHRAS”), GoldenKeys High-tech Materials Co., Ltd., and Anglo-American Platinum. The PET scanner was funded by Wellcome Trust grant 08452/Z/07/Z. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. We thank Lijiang Song and Ivan Prokes for assistance with mass spectrometry and NMR, respectively. Publisher Copyright: {\textcopyright} 2023 The Authors. Published by American Chemical Society",

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T1 - Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy

AU - Imberti, Cinzia

AU - Lok, Jamie

AU - Coverdale, James P.C.

AU - Carter, Oliver W. L.

AU - Fry, Millie E.

AU - Postings, Miles L.

AU - Kim, Jana

AU - Firth, George

AU - Blower, Philip J.

AU - Sadler, Peter J.

N1 - Funding Information: This research was funded by the Wellcome Trust (grant no. 209173/Z/17/Z for C.I.), the Engineering and Physical Sciences Research Council (EPSRC grant no. EP/P030572/1), the Royal Society of Chemistry (grant no. E22-1637945680 for J.P.C.C.), the Wellcome Multiuser Equipment Radioanalytical Facility funded by Wellcome Trust (212885/Z/18/Z), the EPSRC programme for Next Generation Molecular Imaging and Therapy with Radionuclides (EP/S019901/1, “MITHRAS”), GoldenKeys High-tech Materials Co., Ltd., and Anglo-American Platinum. The PET scanner was funded by Wellcome Trust grant 08452/Z/07/Z. For the purpose of open access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. We thank Lijiang Song and Ivan Prokes for assistance with mass spectrometry and NMR, respectively. Publisher Copyright: © 2023 The Authors. Published by American Chemical Society

PY - 2023/12/18

Y1 - 2023/12/18

N2 - A novel photoactivatable Pt(IV) diazido anticancer agent, Pt-succ-DFO, bearing a pendant deferoxamine (DFO) siderophore for radiometal chelation, has been synthesized for the study of its in vivo behavior with radionuclide imaging. Pt-succ-DFO complexation of Fe(III) and Ga(III) ions yielded new heterobimetallic complexes that maintain the photoactivation properties and photocytotoxicity of the parent Pt complex in human cancer cell lines. Radiolabeled Pt-succ-DFO-68Ga (t1/2 = 68 min, positron emitter) was readily prepared under mild conditions and was stable in the dark upon incubation with human serum. PET imaging of Pt-succ-DFO-68Ga in healthy mice revealed a promising biodistribution profile with rapid renal excretion and limited organ accumulation, implying that little off-target uptake is expected for this class of agents. Overall, this research provides the first in vivo imaging study of the whole-body distribution of a photoactivatable Pt(IV) azido anticancer complex and illustrates the potential of radionuclide imaging as a tool for the preclinical development of novel light-activated agents.

AB - A novel photoactivatable Pt(IV) diazido anticancer agent, Pt-succ-DFO, bearing a pendant deferoxamine (DFO) siderophore for radiometal chelation, has been synthesized for the study of its in vivo behavior with radionuclide imaging. Pt-succ-DFO complexation of Fe(III) and Ga(III) ions yielded new heterobimetallic complexes that maintain the photoactivation properties and photocytotoxicity of the parent Pt complex in human cancer cell lines. Radiolabeled Pt-succ-DFO-68Ga (t1/2 = 68 min, positron emitter) was readily prepared under mild conditions and was stable in the dark upon incubation with human serum. PET imaging of Pt-succ-DFO-68Ga in healthy mice revealed a promising biodistribution profile with rapid renal excretion and limited organ accumulation, implying that little off-target uptake is expected for this class of agents. Overall, this research provides the first in vivo imaging study of the whole-body distribution of a photoactivatable Pt(IV) azido anticancer complex and illustrates the potential of radionuclide imaging as a tool for the preclinical development of novel light-activated agents.

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JO - Inorganic Chemistry

JF - Inorganic Chemistry

IS - 50

ER -

Radiometal-Labeled Photoactivatable Pt(IV) Anticancer Complex for Theranostic Phototherapy

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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Projects

Mitochondrial-targeting organometallic catalysts in cancer cells

Cite this