Na⁺ and solute diffusion in aqueous channels of Myverol bicontinuous cubic phase: PGSE NMR and computer modelling

Abstract

The apparent diffusion coefficients of Na ions and the solute 2-fluoroethylamine present in the aqueous domain of a Myverol/water bulk bicontinuous cubic phase (BCP) were measured using pulsed field-gradient spin echo (PGSE) NMR spectroscopy. The measured values were dependent on the diffusion time interval, which is a characteristic of restricted diffusion. The translational motion of Na and water in the aqueous channels of a cubic phase were simulated using a Monte-Carlo random walk algorithm, and the simulation results were compared with those from real PGSE NMR experiments. The simulations indicated that diffusion of Na ions and water would appear to be restricted even on the shortest timescales available to PGSE NMR experiments. The micro-viscosity of the aqueous domain of the BCPs was estimated from the longitudinal relaxation times of Na and 2-fluoroethylamine; this was three times higher than in free solution and suggests one of (but not the only) likely impediments to the release of hydrophilic drugs from stabilised aqueous dispersions of BCPs (cubosomes) when they are used therapeutically in vivo. Monte Carlo simulations of diffusive efflux from cubosomes suggest that the principal impediment to drug release is presented by a surfactant or lipid barrier at the cubosome surface, which separates the BCP aqueous channels from the bulk solution. The dynamics inferred from these studies informs quantitative predictions of drug delivery from cubosomes. Copyright © 2016 John Wiley & Sons, Ltd.

NMR spectroscopy of lipidic cubic phases

“…The diffusion of ions in LCPs is commonly investigated using NMR which can be easily implemented to study the dynamics of hydrophilic species in the aqueous channels of cubic phases and similar structures, as well as measure the ion-transporting efficiency of ionophores. For instance, 23 Na + ions were shown to have a restricted diffusion in a Myverol/water bulk bicontinuous cubic phase (Larkin et al 2017). Coupled with Monte Carlo simulations of diffusive efflux from cubic phase nanoparticles (cubosomes), similar observations were made with 2-fluoroethylamine molecules incubated within a bicontinuous LCP, consistent with a higher microviscosity inside the aqueous channels.…”

Measuring translational diffusion of 15N-enriched biomolecules in complex solutions with a simplified 1H-15N HMQC-filtered BEST sequence

“…This alternative 1 H-N HMQC-filtered sequence provides additional means for the characterization of translational diffusion properties of 15 N-enriched proteins and peptides in solution. The sequence should be applicable to use in complex systems (Barhoum et al 2016), such as protein and ligand complexes (Gossert and Jahnke 2016), protein or peptide in crowded protein solutions (Li et al 2009;Roosen-Runge et al 2011;Wang et al 2010), proteins in detergent micellesa membrane-mimicking media (Andersson et al 2004;Chou et al 2004), and molecules within bicontinuous cubic phases (Eriksson and Lindblom 1993;Larkin et al 2017;Meikle et al 2017;Zabara et al 2017),…”

Water diffusion in complex systems measured by PGSE NMR using chemical shift selective stimulated echo: Elimination of magnetization exchange effects

“…22,23 PGSE NMR has been employed to measure diffusion properties of water, lipids and small drug-like molecules encapsulated in LCPs. 20,22,24,25 The correlations between the release profiles of model drug-like molecules from the LCP matrixes and their diffusion properties as measured by PGSE NMR have also been explored. 20 In this report, we firstly present an exchange induced zero-crossing phenomenon, for signal attenuation of water diffusion in LCPs observed using the standard STE sequence.…”