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

Abstract

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(IV) to Pt(II) promoted by MGd occurs in cell culture as well, leading to an increase in the antiproliferative activity of the Pt(IV) species 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(IV) prodrugs.

Cancer‐Specific, Intracellular, Reductive Activation of Anticancer PtIV Prodrugs

“…These data are in agreement with the intracellular release of active drug cisplatin from 8 . It should be mentioned that the recently published approach for reduction of Pt IV prodrugs mediated by motexafin gadolinium relies on their activation exclusively outside of cells . Therefore, in contrast to our hybrid, these Pt IV complexes are expected to exhibit low activity towards cisplatin‐resistant cells analogously to the parent Pt II drugs.…”

Hypoxia-targeted drug delivery

“…In follow up in vitro studies, it was discovered that texaphyrin participated as redox mediators in the reduction and activation of Pt(IV) prodrugs in the presence of cancer cells. 398 Over the past several years, a number of other efforts beyond those associated with platinum complex and its analogues have been devoted with a view to meeting the challenge of producing modified platinum agents with targeting capabilities. Generally, one or two biologically active non-DNA targeting moieties are included within the Pt(IV) coordination sphere.…”

Riboflavin as a bioorthogonal photocatalyst for the activation of a PtIV prodrug

“…However, at this stage, we cannot exclude that these strong and specific interactions could significantly lower the redox potential of 1 and cause direct reduction of the prodrug once the Rf -adducts are formed. 35 , 36 Calculated binding energies for 1 - Rf H 2 and 1 - Rf H – adducts are in the range of 52–69 kcal mol –1 , indicating that these transient species are strongly stabilized and may bestow unique selectivity to the Rf / 1 catalyst/substrate pair ( vide infra ).…”