Activation of Platinum(IV) Prodrugs By Motexafin Gadolinium as a Redox Mediator

Water-soluble platinum(IV) prodrugs, which proved kinetically stable to reduction in the presence of physiological concentration of ascorbate, were quickly reduced to their active form, oxaliplatin, when co-incubated with a macrocycle metallotexaphyrin (i.e., Motexafin Gadolinium (MGd)). The reduction of Pt^IVto Pt^IIpromoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt^IVspecies in question. The mediated effect is proportional to the concentration of MGd and gives rise to an enhancement when the prodrug is relatively hydrophilic. MGd is known to localize/accumulate preferentially in tumor tissues. Thus, the present “activation by reduction” approach may allow for the cancer-selective enhancement in the cytotoxicity of Pt^IVprodrugs.