Evidence that fodipir (DPDP) binds neurotoxic Pt2+ with a high affinity: An electron paramagnetic resonance study

Abstract

Oxaliplatin typically causes acute neuropathic problems, which may, in a dose-dependent manner, develop into a chronic form of chemotherapy-induced peripheral neuropathy (CIPN), which is associated with retention of Pt²⁺ in the dorsal root ganglion. A clinical study by Coriat and co-workers suggests that co-treatment with mangafodipir [Manganese(II) DiPyridoxyl DiPhosphate; MnDPDP] cures ongoing CIPN. These authors anticipated that it is the manganese superoxide dismutase mimetic activity of MnDPDP that explains its curative activity. However, this is questionable from a pharmacokinetic perspective. Another, but until recently undisclosed possibility is that Pt²⁺ outcompetes Mn²⁺/Ca²⁺/Zn²⁺ for binding to DPDP or its dephosphorylated metabolite PLED (diPyridoxyL EthylDiamine) and transforms toxic Pt²⁺ into a non-toxic complex, which can be readily excreted from the body. We have used electron paramagnetic resonance guided competition experiments between MnDPDP (¹⁰logK_ML ≈ 15) and K₂PtCl₄, and between MnDPDP and ZnCl₂ (¹⁰logK_ML ≈ 19), respectively, in order to obtain an estimate the ¹⁰logK_ML of PtDPDP. Optical absorption spectroscopy revealed a unique absorption line at 255 nm for PtDPDP. The experimental data suggest that PtDPDP has a higher formation constant than that of ZnDPDP, i.e., higher than 19. The present results suggest that DPDP/PLED has a high enough affinity for Pt²⁺ acting as an efficacious drug in chronic Pt²⁺-associated CIPN.