Plasma membrane lipid bilayer is druggable: Selective delivery of gemcitabine-squalene nano-medicine to cancer cells.

Up to now the lipid bilayers were rarely considered as targets in cancer therapy despite pronounced differences in lipid composition between plasma membranes of benign and malignant cells. In this study we demonstrate that the lipid bilayer of the plasma membrane is druggable and suitable for facilitating selective delivery of amphiphilic gemcitabine-squalene nanomedicines to cancer cells. Data from radioactive assays, fluorescent membrane probes and molecular dynamics simulations provide evidence of selective accumulation of gemcitabine-squalene in the plasma membranes with disrupted lipid asymmetry and its subsequent preferential uptake by malignant cells. This causes pronounced cytotoxicity on cancer cells in comparison to their benign counterparts originating from the same tissue.

Influence of Substrate Hydrophilicity on Structural Properties of Supported Lipid Systems on Graphene, Graphene Oxides, and Silica.

Pristine graphene, a range of graphene oxides, and silica substrates were used to investigate the effect of surface hydrophilicity on supported lipid bilayers by means of all-atom molecular dynamics simulations. Supported 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayers were found in close-contact conformations with hydrophilic substrates with as low as 5% oxidation level, while self-assembled monolayers occur on pure hydrophobic graphene only. Lipids and water at the surface undergo large redistribution to maintain the stability of the supported bilayers. Deposition of bicelles on increasingly hydrophilic substrates shows the continuous process of reshaping of the supported system and makes intermediate stages between self-assembled monolayers and supported bilayers. The bilayer thickness changes with hydrophilicity in a complex manner, while the number of water molecules per lipid in the hydration layer increases together with hydrophilicity.

Curvature increases permeability of the plasma membrane for ions, water and the anti-cancer drugs cisplatin and gemcitabine.

In this work the permeability of a model asymmetric plasma membrane, for ions, water and the anti-cancer drugs cisplatin and gemcitabine is studied by means of all-atom molecular dynamics simulations. It is shown for the first time that permeability of the highly curved membrane increases from one to three orders of magnitude upon membrane bending depending on the compound and the sign of curvature. Our results suggest that the membrane curvature could be an important factor of drug translocation through the membrane.

The asymmetry of plasma membranes and their cholesterol content influence the uptake of cisplatin.

The composition of the plasma membrane of malignant cells is thought to influence the cellular uptake of cisplatin and to take part in developing resistance to this widespread anti-cancer drug. In this work we study the permeation of cisplatin through the model membranes of normal and cancer cells using molecular dynamics simulations. A special attention is paid to lipid asymmetry and cholesterol content of the membranes. The loss of lipid asymmetry, which is common for cancer cells, leads to a decrease in their permeability to cisplatin by one order of magnitude in comparison to the membranes of normal cells. The change in the cholesterol molar ratio from 0% to 33% also decreases the permeability of the membrane by approximately one order of magnitude. The permeability of pure DOPC membrane is 5-6 orders of magnitude higher than one of the membranes with realistic lipid composition, which makes it as an inadequate model for the studies of drug permeability.

The influence of curvature on the properties of the plasma membrane. Insights from atomistic molecular dynamics simulations.

In this work we conduct a systematic analysis of the influence of curvature on various properties of a realistic model of mammalian plasma membrane with asymmetric lipid content of monolayers and a realistic concentration of cholesterol. In order to do this we developed new technique for simulating membranes with the global membrane curvature restricted to any desirable value while keeping free lateral diffusion of the lipids and without introducing artifacts or perturbing the membrane structure. We show that the thickness of the hydrophobic core of the concave monolayer decreases by approximately 1.3 Å in comparison to that of the flat membrane, while the thickness of the convex monolayer does not change. The order parameter of the lipid tails decreases significantly in the certain layers of the curved membrane. The area per lipid increases in the convex monolayer and decreases in the concave monolayer. The cholesterol inclination angle decreases when the curvature of a particular monolayer changes from concave to convex. The amount of cholesterol in the minor fraction located between the membrane leaflets is zero in the membrane with positive curvature and increases to 1.7% in the flat membrane and to 2.5% in the membrane with negative curvature.