The Design and Synthesis of Stabilised Cis- and Trans-Platinum (IV) Complexes for Targeted Drug Delivery

Abstract

Platinum(IV) complexes are a promising class of pro-drugs which may bypass the problems associated with their platinum(II) counterparts, such as cisplatin and oxaliplatin. However, any pharmacokinetic advantages conferred by the platinum(IV) oxidation state are often lost due to the rapid reduction of these complexes en route to the tumour site. Despite several platinum(IV) complexes, such as satraplain, undergoing extensive clinical trials, no platinum(IV) complexes have been approved for clinical use to date. Recently, platinum(IV) complexes with a cis-diamminetetracarboxylato coordination sphere were shown to exhibit unusual resistance to reduction by L-ascorbate that did not correlate with their electrochemical reduction potential. In this study, we further investigated the influence of the overall coordination and geometry of platinum(IV) complexes on their resistance to reduction in a range of endogenous and biological reductants and biological environments using various spectroscopic and biological techniques such as XANES, SXFM, XRF μCT, 1D and 2D NMR and GF-AAS. We report the resistance to reduction exhibited by cis and trans-diamminetetracarboxylato platinum(IV) complexes, using 1H NMR and XANES spectroscopy. Interestingly, this class of platinum(IV) complex appears to be usually resistant to reduction in the presence of excess endogenous reductants, but are rapidly reduced within DLD-1 human colon cancer cells. A series of 13C labelled platinum(IV) complexes with various coordination spheres and geometries were synthesised. The reduction of these complexes by aqueous cellular extracts of DLD-1 cells were observed to undergo several reduction pathways. Finally, we report several design and synthetic strategies for the development of targeted drug delivery for classical and non-classical platinum(IV) pro-drugs that can potentially bypass uptake and reduction by red blood cells and selectively deliver platinum(IV) complexes to specific tumour environments.