Hypoxia-Responsive Cobalt Complexes in Tumor Spheroids: Laser Ablation Inductively Coupled Plasma Mass Spectrometry and Magnetic Resonance Imaging Studies

O'Neill, ES; Kaur, A; Bishop, DP; Shishmarev, D; Kuchel, PW; Grieve, SM; Figtree, GA; Renfrew, AK; Bonnitcha, PD; New, EJ

Hypoxia-Responsive Cobalt Complexes in Tumor Spheroids: Laser Ablation Inductively Coupled Plasma Mass Spectrometry and Magnetic Resonance Imaging Studies

O'Neill, ES Kaur, A

Bishop, DP

Shishmarev, D Kuchel, PW Grieve, SM Figtree, GA Renfrew, AK Bonnitcha, PD New, EJ

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Publication Type:: Journal Article
Citation:: Inorganic Chemistry, 2017, 56 (16), pp. 9860 - 9868
Issue Date:: 2017-08-21

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Field	Value	Language
dc.contributor.author	O'Neill, ES	en_US
dc.contributor.author	Kaur, A https://orcid.org/0000-0002-0898-875X	en_US
dc.contributor.author	Bishop, DP https://orcid.org/0000-0002-6533-4410	en_US
dc.contributor.author	Shishmarev, D	en_US
dc.contributor.author	Kuchel, PW	en_US
dc.contributor.author	Grieve, SM	en_US
dc.contributor.author	Figtree, GA	en_US
dc.contributor.author	Renfrew, AK	en_US
dc.contributor.author	Bonnitcha, PD	en_US
dc.contributor.author	New, EJ	en_US
dc.date.issued	2017-08-21	en_US
dc.identifier.citation	Inorganic Chemistry, 2017, 56 (16), pp. 9860 - 9868	en_US
dc.identifier.issn	0020-1669	en_US
dc.identifier.uri	http://hdl.handle.net/10453/124487
dc.description.abstract	© 2017 American Chemical Society. Dense tumors are resistant to conventional chemotherapies due to the unique tumor microenvironment characterized by hypoxic regions that promote cellular dormancy. Bioreductive drugs that are activated in response to this hypoxic environment are an attractive strategy for therapy with anticipated lower harmful side effects in normoxic healthy tissue. Cobalt bioreductive pro-drugs that selectively release toxic payloads upon reduction in hypoxic cells have shown great promise as anticancer agents. However, the bioreductive response in the tumor microenvironment must be better understood, as current techniques for monitoring bioreduction to Co(II) such as X-ray absorption near-edge structure and extended X-ray absorption fine structure provide limited information on speciation and require synchrotron radiation sources. Here, we present magnetic resonance imaging (MRI) as an accessible and powerful technique to monitor bioreduction by treating the cobalt complex as an MRI contrast agent and monitoring the change in water signal induced by reduction from diamagnetic Co(III) to paramagnetic Co(II). Cobalt pro-drugs built upon the tris(2-pyridylmethyl)amine ligand scaffold with varying charge were investigated for distribution and activity in a 3D tumor spheroid model by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and MRI. In addition, paramagnetic 1H NMR spectroscopy of spheroids enabled determination of the speciation of activated Co(II)TPAx complexes. This study demonstrates the utility of MRI and associated spectroscopy techniques for understanding bioreductive cobalt pro-drugs in the tumor microenvironment and has broader implications for monitoring paramagnetic metal-based therapies.	en_US
dc.relation.ispartof	Inorganic Chemistry	en_US
dc.relation.isbasedon	10.1021/acs.inorgchem.7b01368	en_US
dc.subject.classification	Inorganic & Nuclear Chemistry	en_US
dc.subject.mesh	Spheroids, Cellular	en_US
dc.subject.mesh	Tumor Cells, Cultured	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Cattle	en_US
dc.subject.mesh	Sheep	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Cobalt	en_US
dc.subject.mesh	Water	en_US
dc.subject.mesh	Prodrugs	en_US
dc.subject.mesh	Contrast Media	en_US
dc.subject.mesh	Ligands	en_US
dc.subject.mesh	Mass Spectrometry	en_US
dc.subject.mesh	Coordination Complexes	en_US
dc.subject.mesh	Proton Magnetic Resonance Spectroscopy	en_US
dc.subject.mesh	Tumor Hypoxia	en_US
dc.title	Hypoxia-Responsive Cobalt Complexes in Tumor Spheroids: Laser Ablation Inductively Coupled Plasma Mass Spectrometry and Magnetic Resonance Imaging Studies	en_US
dc.type	Journal Article
utslib.citation.volume	16	en_US
utslib.citation.volume	56	en_US
utslib.for	0302 Inorganic Chemistry	en_US
utslib.for	0904 Chemical Engineering	en_US
utslib.for	0399 Other Chemical Sciences	en_US
utslib.for	0306 Physical Chemistry (incl. Structural)	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
utslib.copyright.status	closed_access
pubs.issue	16	en_US
pubs.publication-status	Published	en_US
pubs.volume	56	en_US

Abstract:

© 2017 American Chemical Society. Dense tumors are resistant to conventional chemotherapies due to the unique tumor microenvironment characterized by hypoxic regions that promote cellular dormancy. Bioreductive drugs that are activated in response to this hypoxic environment are an attractive strategy for therapy with anticipated lower harmful side effects in normoxic healthy tissue. Cobalt bioreductive pro-drugs that selectively release toxic payloads upon reduction in hypoxic cells have shown great promise as anticancer agents. However, the bioreductive response in the tumor microenvironment must be better understood, as current techniques for monitoring bioreduction to Co(II) such as X-ray absorption near-edge structure and extended X-ray absorption fine structure provide limited information on speciation and require synchrotron radiation sources. Here, we present magnetic resonance imaging (MRI) as an accessible and powerful technique to monitor bioreduction by treating the cobalt complex as an MRI contrast agent and monitoring the change in water signal induced by reduction from diamagnetic Co(III) to paramagnetic Co(II). Cobalt pro-drugs built upon the tris(2-pyridylmethyl)amine ligand scaffold with varying charge were investigated for distribution and activity in a 3D tumor spheroid model by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and MRI. In addition, paramagnetic 1H NMR spectroscopy of spheroids enabled determination of the speciation of activated Co(II)TPAx complexes. This study demonstrates the utility of MRI and associated spectroscopy techniques for understanding bioreductive cobalt pro-drugs in the tumor microenvironment and has broader implications for monitoring paramagnetic metal-based therapies.

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http://hdl.handle.net/10453/124487