A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models

Here we describe
a new approach for tumor targeting in which augmented
concentrations of Fe­(II) in cancer cells and/or the tumor microenvironment
triggers drug release from an Fe­(II)-reactive prodrug conjugate. The
1,2,4-trioxolane scaffold developed to enable this approach can in
principle be applied to a broad range of cancer therapeutics and is
illustrated here with Fe­(II)-targeted forms of a microtubule toxin
and a duocarmycin-class DNA-alkylating agent. We show that the intrinsic
reactivity/toxicity of the duocarmycin analog is masked in the conjugated
form and this greatly reduced toxicity in mice. This in turn permitted
elevated dosing levels, leading to higher systemic exposure and a
significantly improved response in tumor xenograft models. Overall
our results suggest that Fe­(II)-dependent drug delivery via trioxolane
conjugates could have significant utility in expanding the therapeutic
index of a range of clinical and preclinical stage cancer chemotherapeutics.