Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer

ABSTRACT

Oxygen supply – demand imbalances can render proliferating cells acutely or chronically hypoxic.  In cancer cells, hypoxia-induced pathophysiological changes give rise to genetic changes that lead to treatment-resistant, aggressive phenotypes. The reduced curability of hypoxic tumours by radiotherapy is one of consequent challenges, but their hypoxia also offers unique, exploitable properties.  Nitroimidazoles, for example, capitalize on oxygen-sensitive reductive activation to achieve hypoxia-selective localization for theranostic consequence.  The discovery of 2-nitroimidazole (azomycin) heralded the development of many drugs, including effective radiosensitizers of hypoxic cells.  These electron-affinic, reductively bioactivated nitroheterocyclics undergo initial oxygen-reversible, enzymatic one-electron reductions that lead to the formation of molecular adducts that impair vital molecular processes.  Accumulation of radiolabelled adducts within hypoxic cells creates localized, imageable signals and/or radiotherapeutic (MRT) concentrations of the radiopharmaceutical.

The theranostic potential of hypoxia-targeted organometalic nitroimidazole derivatives is imparted by the radioisotope of the selected metal – main group metals (Al, Ga, In, Zn), transition metals (Cu, Tc, Re, Zn) or lanthanides ( Gd, Lu).  Of these, the transition element complexes of Cu and Tc have received the most attention.  Selected ligands comprise a broad range of mono- or poly-dentate, linear or cyclic chelators, which have been modified with hypoxia-selective nitroimidazoles or nitrotriazoles tethered by a variety of linker moieties.

These metal-nitroimidazole complexes have one or more reducible centres (i.e., nitroimidazole; transition metal core), each of which has characteristic redox properties and consequently, unique interactions inside target (hypoxic) and normoxic tissues.  In theory, complexes with reducible metal cores (i.e., transition metals) and reducible targeting vectors (i.e., nitroimidazole) potentially offer greater selectivity and sensitivity for hypoxic tissues than either reducible metal-complexes alone or the nitroimidazole without the reducible metal centre.

The current review focuses on the design, radiolabelling chemistry and hypoxia-selective properties of those organometallic complexes that include nitroimidazoles as their bioactive targeting moiety.

Keywords: hypoxia; metal-nitroimidazole complexes; oxygen mimetics; bioreductive activation; molecular adducts; hypoxia-selective theranosis (Therapy + diagnosis).

Citation: Ricardo CL, Kumar P, Wiebe LI. Bifunctional Metal – Nitroimidazole Complexes for Hypoxia Theranosis in Cancer. Journal of Diagnostic Imaging in Therapy. 2015; 2(1): 103-158.

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DOI: http://dx.doi.org/10.17229/jdit.2015-0415-015

Copyright: © 2015 Ricardo CL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are cited.

Received: 18 March 2015 | Revised: 13 April 2015 | Accepted: 14 April 2015

Published Online 15 April 2015  http://www.openmedscience.com

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JDIT-2015-0415-015