Tuning drug ratios in multi-action platinum(IV) therapeutics

Platinum(II)-based anticancer drugs are an inherent part of nearly every second chemotherapeutic invention and their high synergism with modern immune checkpoint inhibitors will keep them essential in the future. However, drug resistance and the occurrence of adverse effects are major limitations. A very promising approach to overcome these drawbacks is the development of platinum(IV) prodrugs, which are kinetically more inert, leading to a lower reactivity with biomolecules, and hence, to a reduced number of undesirable side reactions. Inside the tumor tissue, the platinum(IV) complexes are "activated by reduction" with formation of the highly active platinum(II) analogs. The development of platinum(IV) multi-action prodrugs, bearing additional bioactive moieties is currently an important research strategy to allow highly active combination therapy approaches with reduced adverse effects. However, one of the main problems of these multi- action platinum(IV) drugs is that the dose ratio of the platinum core to the bioactive ligand is often inappropriate. Due to severe side effects of the released platinum(II) drugs, the platinum(IV) complexes can only be applied at limited concentrations, frequently insufficient to exploit the full potential of the additional bioactive drug. In this project we will increase the platinum/bioactive drug ratio by the development of novel platinum(IV) complexes with a small dendritic unit harboring three molecules of the synergistic bioactive drug (1:3 complexes). Only after reduction of the platinum(IV) core, the bioactive drugs will be released. This is expected to result in distinctly improved synergistic anticancer activity. As additional bioactive moieties an immunomodulator (indoximod) or the resistance modulator L- buthionine-S,R-sulfoximine (BSO) will be attached. In addition, derivatives will be synthesized that can endogenously bind to serum albumin which acts as a natural nano-transporter. All novel complexes will be in detail physico-chemically analyzed and biologically investigated e.g. using cell culture studies, pharmacokinetic investigations, tumor accumulation as well as anticancer activity in mouse models. The project will be coordinated by the synthetic chemist Prof. Christian Kowol from the Institute of Inorganic Chemistry, University of Vienna. He will work in close collaboration with the cell biologist Prof. Petra Heffeter from the Center of Cancer Research, Medical University of Vienna. This cooperation is already very well established and resulted in many joint research grants and high-level publications. Taken together, the here presented concept introduces a completely new platform for the design of multi-targeted platinum(IV) complexes with high flexibility for fine-tuning of the ratio of platinum drug and the additional bioactive moiety. After the herein executed proof-of-concept studies, this approach can be extended to the development of a broad range of novel platinum(IV) complexes.