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

Inorg Chem. 2017 Aug 21;56(16):9860-9868. doi: 10.1021/acs.inorgchem.7b01368. Epub 2017 Aug 2.


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.

MeSH terms

  • Animals
  • Cattle
  • Cobalt / chemistry*
  • Contrast Media / chemical synthesis
  • Contrast Media / pharmacology*
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / pharmacology*
  • Humans
  • Ligands
  • Mass Spectrometry / methods
  • Prodrugs / chemical synthesis
  • Prodrugs / pharmacology*
  • Proton Magnetic Resonance Spectroscopy / methods
  • Sheep
  • Spheroids, Cellular / physiology*
  • Tumor Cells, Cultured
  • Tumor Hypoxia / physiology
  • Water / chemistry


  • Contrast Media
  • Coordination Complexes
  • Ligands
  • Prodrugs
  • Water
  • Cobalt