Quantitative measurement of the reduction of platinum(IV) complexes using X-ray absorption near-edge spectroscopy (XANES).

Abstract

The platinum(II) drugs cisplatin, carboplatin and oxaliplatin are usefully employed against a range of malignancies, but toxicities and resistance have spurred the search for improved analogs. This has included investigation of the platinum(IV) oxidation state, which provides greater kinetic inertness. It is generally accepted that Pt(IV) complexes must be reduced to Pt(II) for activation. As such, the ability to monitor reduction of Pt(IV) complexes is critical to guiding the design of candidates, and providing mechanistic understanding. Here we report in full that the white line height of X-ray absorption near-edge spectra (XANES) of Pt complexes, normalized to the post-edge minima, can be used to quantitatively determine the proportion of each oxidation state in a mixture. A series of Pt(IV) complexes based on the Pt(II) complexes cisplatin and transplatin were prepared with chlorido, acetato or hydroxido axial ligands, and studies into their reduction potential and cytotoxicity against A2780 human ovarian cancer cells were performed, demonstrating the relationship between reduction potential and cytotoxicity. Analysis of white line height demonstrated a clear and consistent difference between Pt(II) (1.52 ± 0.05) and Pt(IV) (2.43 ± 0.19) complexes. Reduction of Pt(IV) complexes over time in cell growth media and A2780 cells was observed by XANES, and shown to correspond with their reduction potentials and cytotoxicities. We propose that this method is useful for monitoring reduction of metal-based drug candidates in complex biological systems.

• Authors: Matthew D Hall, Helen L Daly, Jenny Z Zhang, Mei Zhang, Rebecca A Alderden, Daniel Pursche, Garry J Foran, Trevor W Hambley
• Journal: Metallomics : integrated biometal science (Metallomics) Vol. 4 Issue 6 Pg. 568-75 (Jun 2012) ISSN: 1756-591X [Electronic] England
• PMID: 22569908 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Culture Media
• Organoplatinum Compounds
• Oxaliplatin
• Carboplatin
• Cisplatin

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Carboplatin (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cisplatin (chemistry, pharmacology)
• Culture Media
• Humans
• Organoplatinum Compounds (chemistry, pharmacology)
• Oxaliplatin
• Oxidation-Reduction
• X-Ray Absorption Spectroscopy (methods)