Breakdown of classical paradigms in lipid membranes. Part II: The permeability paradox.

Water soluble non electrolytes alter the density and the compressibility of the lipid membrane according to its ability to permeate. Glucose, a non-permeant, accumulates at the interphase binding to the PO2- groups promoting water extrusion and decreasing the specific volume and the compressibility without altering the vesicle size. Permeant as glycerol produces a lower change in agreement with its partial permeation. This behavior suggests a reduction in interfacial free volume and a restriction of area fluctuations while the membrane remains in the liquid-crystalline phase correlated with the shift of the distribution of water populations in PC membranes towards connected H bond populations. The polarization of the interphase increases from water to glucose congruent with an increase with the number of H-bonding groups reflected in changes in the water bands. Isotonic glycerol uptake presents a near-ideal Fickian diffusion mechanism, when vesicle swells due to displacement of glucose at the interface and expansion of the hydrated carbonyl population. In contrast, hypertonic permeation shows a non-Fickian transport regime (n = 1.16) due to the initial osmotic shrinkage. In this condition, the activation energy of permeation is lower than the isotonic one correlated to a ten-fold increase in unrelaxed water microstates, related to the exposure of hydrophobic regions and the creation of packing defects along the C=O plane. The results validate a model of membrane interphase of hydrated headgroups dissolved in loose, labile water providing a powerful framework for the intelligent design of smart liposomal controlled delivery systems triggered by solute-induced release.