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Keywords:

  • cobalt;
  • drug delivery;
  • hydroxamates;
  • hypoxia;
  • X-ray diffraction

Abstract

We report a potential means of selectively delivering matrix metalloproteinase (MMP) inhibitors to target tumour sites by use of a bioreductively activated CoIII carrier system. The carrier, comprising a CoIII complex of the tripodal ligand tris(methylpyridyl)amine (tpa), was investigated with the antimetastatic MMP inhibitor marimastat (mmstH2). The X-ray crystal structure of [Co(mmst)(tpa)]ClO4⋅4 H2O was determined and two-dimensional NMR revealed the existence of two isomeric forms of the complex in solution. Electrochemical analysis showed that the reduction potential of the complex is suitable for it to be bioreductively activated at hypoxic tumour sites. In vitro assays confirmed the stability of the prodrug in solution prior to reduction and revealed very low cytotoxicity against A2780 cells. In vivo testing in mice showed a higher level of tumour-growth inhibition by the complex than by free marimastat. Both free marimastat and and its CoIII complex increased metastasis in the model used, with the complex significantly more active.