抄録
Molecular dynamics of the drug delivery to fluid lipid bilayer membranes is crucial as a primary stage of the bioactivity in the cell. Lipid bilayer membrane, as a platform of vital functions, is a dynamic structure where molecules are always fluctuating under physiological conditions. The mechanism of drug deliveries is related to the molecular dynamics in such soft, fluid membrane interface.
To gain insight into molecular mechanisms of drug deliveries in a noninvasive manner, we develop the method to monitor dynamic properties of drugs and lipid components in membranes without labeled nuclei, by applying multinuclear high-resolution solution NMR in combination with the pulsed-field-gradient (PFG) technique. PFG NMR spectroscopy is a versatile method to elucidate the molecular motion in a natural manner. We have quantified the diffusivity, the kinetics of membrane binding, and the bound fraction of the drug in situ by using large unilamellar vesicles of egg phosphatidylcholine as model cell membranes. The PFG method unveils the bound component after the preferential decay of the free component at the high field gradient, where the chemical shift difference between these components is not enough to distinguish from each other. The rate constants of the binding and dissociation of the drug are determined by using the solution of the Bloch equation with diffusion and exchange terms. The combination of 1D and PFG NMR serves to quantify the kinetics of membrane binding where the bound and the free components are unable to distinguish because of the rapid exchange on the NMR timescale. A small-sized 5-fluorouracil and fluorinated bisphenol A are used as a model drug.
