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Evidence that fodipir (DPDP) binds neurotoxic Pt2+ with a high affinity: An electron paramagnetic resonance study
Linköping University, Department of Physics, Chemistry and Biology, Surface Physics and Chemistry. Linköping University, Department of Physics, Chemistry and Biology, Biomolecular and Organic Electronics. Linköping University, Faculty of Science & Engineering.ORCID iD: 0000-0001-7640-8086
Linköping University, Department of Physics, Chemistry and Biology, Sensor and Actuator Systems. Linköping University, Faculty of Science & Engineering.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 15813Article in journal (Refereed) Published
Abstract [en]

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 (10logKML ≈ 15) and K2PtCl4, and between MnDPDP and ZnCl2 (10logKML ≈ 19), respectively, in order to obtain an estimate the 10logKML 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019. Vol. 9, article id 15813
National Category
Biophysics Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-161652DOI: 10.1038/s41598-019-52248-9ISI: 000493716000014PubMedID: 31676855Scopus ID: 2-s2.0-85074277794OAI: oai:DiVA.org:liu-161652DiVA, id: diva2:1367782
Funder
Medical Research Council of Southeast Sweden (FORSS), 85191
Note

Funding agencies: Medical Research Council of Southeast Sweden [FORSS-85191]; Karlsson-Tuner Invest AS, Norway

Available from: 2019-11-05 Created: 2019-11-05 Last updated: 2019-11-19Bibliographically approved

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Stehr, Jan EricLundström, IngemarKarlsson, Jan Olof G.

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Surface Physics and ChemistryBiomolecular and Organic ElectronicsFaculty of Science & EngineeringSensor and Actuator SystemsDivision of Drug ResearchFaculty of Medicine and Health Sciences
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