Correlation of [RuCl₃(dppb)(VPy)] Cytotoxicity with its Effects on the Cell Membranes: An Investigation Using Langmuir Monolayers as Membrane Models

Abstract

One of the major challenges in drug design is to identify compounds with potential toxicity toward target cells, preferably with molecular-level understanding of their mode of action. In this study, the antitumor property of a ruthenium complex, mer-[RuCl 3 (dppb)(VPy)] (dppb =1,4-bis(diphenylphosphine)butane and VPy = 4-vinylpyridine) (RuVPy), was analyzed. Results showed that this compound led to a mortality rate of 50% of HEp-2 cell with 120 ± 10 μmol L −1 , indicating its high toxicity. Then, to prove if its mode of action is associated with its interaction with cell membranes, Langmuir monolayers were used as a membrane model. RuVPy had a strong effect on the surface pressure isotherms, especially on the elastic properties of both the zwitterionic dipalmitoylphosphatidylcholine (DPPC) and the negatively charged dipalmitoylphosphatidylglycerol (DPPG) phospholipids. These data were confirmed by polarization-modulated infrared reflection−absorption spectroscopy (PM-IRRAS). In addition, interactions between the positive group from RuVPy and the phosphate group from the phospholipids were corroborated by density functional theory (DFT) calculations, allowing the determination of the Ru complex orientation at the air−water interface. Although possible contributions from receptors or other cell components cannot be discarded, the results reported here represent evidence for significant effects on the cell membranes which are probably associated with the high toxicity of RuVPy.

PM-IRRAS Studies of DMPC Bilayers Supported on Au(111) Electrodes Modified with Hydrophilic Monolayers of Thioglucose

“…The Langmuir technique allows for the formation of amphiphilic monolayers at the air–water interface and therefore has been widely used to study the interactions of a wide variety of different species, such as drugs, toxins, peptides, proteins, or other biologically important molecules, with simplified biological model membranes. − These molecule–membrane interactions are monitored at the air–water interface by measuring changes in the collapse pressure, compression modulus, and area per molecule. However, these measurements are typically limited to monolayer films and do not provide molecular level information about the effects that these species have on the individual film within the monolayer.…”

Interactions of bioactive molecules & nanomaterials with Langmuir monolayers as cell membrane models

“…In order to verify whether its toxicity is related to its interaction with cell membranes, it was investigated in an artificial membrane modeled as a Langmuir monolayer [213]. Strong influence of the drug on fluidity of both DPPC and DPPG monolayers results mainly from electrostatic interactions in the phospholipids head group region, although some disturbances in the alkyl chain order were also evidenced with PM-IRRAS.…”

Insight into the Molecular Mechanism of Surface Interactions of Phosphatidylcholines─Langmuir Monolayer Study Complemented with Molecular Dynamics Simulations

“…It enabled, among others, to find molecular targets of many bioactive molecules (e.g., drugs, for example, antitumor lipids, abbr. antitumor lipids (ATLs), antimicrobial agents, or food supplements–unsaturated fatty acids or stanols), their mechanism of action − and the reason for their selectivity , or toxicity. − It also allowed us to understand how changing the composition of the membrane and the mutual proportions of its components (e.g., cholesterol-to-phospholipid ratio; sphingolipid content; unsaturation of the phospholipids fatty acids) changes the stiffness of the membranes. Such variations occur in the physiological conditions (for example, when following a specific diet, taking various medications, or even during physical activity), as well as are characteristic for the development of many pathological effects (related to cancer or other diseases, like anemia, or in poisoning (e.g., with ethanol)).…”