Molecular Dynamics Simulation of Passive Diffusion across a Human Breast Cancer Cell Membrane Model. Comparison between Cisplatin and Its Pt(IV) Derivatives.

The efficacy of platinum(II) drugs, despite their wide use in clinical practice, is seriously limited by their well-known drawbacks. Octahedral Pt(IV) congeners are considered a sort of Holy Grail in cancer research as, being significantly more inert, they should be able to overcome the limitations of current platinum-based drugs, such as resistance and side effects, acting as prodrugs. Additionally, their anticancer activity can be tuned through a proper choice of the axial ligands released inside cancer cells when these compounds are reduced, making them even capable of potentially working as multiaction agents. However, despite their very satisfactory anticancer effects, no Pt(IV) complex has been approved for clinical use. As cell membrane permeation is the critical step, very poorly understood, of the whole mechanism of action of any drug, the investigation of the eventual differences in behavior between four-coordinate Pt(II) and six-coordinate Pt(IV) complexes when they diffuse in a lipid bilayer might be of significant relevance. The outcomes of a biased molecular dynamics (MD) investigation of the permeation of cisplatin and three simple cisplatin Pt(IV) derivatives through a membrane model prototype of human breast cancer cells are illustrated here. This comparative analysis of Pt(II) and Pt(IV) complex passive diffusion has been carried out with the aim of gaining indications about the factors that play a role in favoring or hindering membrane penetration and, ultimately, in determining the efficacy of their anticancer action.