Date Published: May 7, 2018
Publisher: Royal Society of Chemistry
Author(s): L. M. Frensemeier, J. Mayr, G. Koellensperger, B. K. Keppler, C. R. Kowol, U. Karst.
A novel analytical approach for the identification/quantification of the reduction products of platinum(iv) complexes is presented.
Platinum-containing anticancer drugs represent one of the main classes of chemotherapeutics1–3 and the Pt(ii) derivatives cisplatin, carboplatin and oxaliplatin are clinically approved worldwide. Despite their success in the treatment of diverse types of cancer, severe side effects are frequently associated with this kind of therapy.1,4,5 Consequently, current research focuses on the development of alternative Pt compounds entailing less adverse effects. The design and application of Pt(iv) prodrugs is one main approach that aims at achieving this goal.6,7 In contrast to the Pt(ii) complexes, Pt(iv) compounds bear two additional axial ligands and are kinetically more stable. Moreover, the introduction of appropriate axial targeting ligands enables a more tumor-selective drug design.6–11 Reduction of the prodrugs favorably occurs in the reductive milieu of the tumor tissue with formation of the active Pt(ii) drug.2,3,12–17 Thereby, the reduction efficiency is dependent on both the equatorial and axial ligands.2,6,18 Conventionally, the reduction behavior is studied with a reducing agent such as ascorbate in buffered solution or via cyclic voltammetry (CV).18–21 In the case of CV, usually solely the redox potentials are estimated without any structural information about the formed products. Using reductants and subsequent mass spectrometric (MS) or nuclear magnetic resonance (NMR) analysis may allow for the identification of at least the main product(s). However, this method is often only successful after isotopic labeling of the ligands and additionally solely for Pt(iv) complexes possessing a cisplatin-like equatorial core structure, since in the case of oxaliplatin- or carboplatin-based Pt(iv) derivatives, the reduction rate with ascorbate is very slow.19,22
Taken together, the here presented EC-LC-MS technology has proven to serve as the first method which allows the fast investigation of the reduction behavior of Pt(iv) complexes as well as the product identification and quantification. Further studies will show the suitability of this method also for other bioactive metal complexes, which are activated by reduction such as Ru(iii) or Co(iii) compounds.
There are no conflicts to declare.