Notman Rebecca, den Otter Wouter K, Noro Massimo G, Briels W J, Anwar Jamshed
Molecular Biophysics, Division of Pharmaceutical Science, King's College London, London, United Kingdom.
Biophys J. 2007 Sep 15;93(6):2056-68. doi: 10.1529/biophysj.107.104703. Epub 2007 May 18.
The lipids of the topmost layer of the skin, the stratum corneum, represent the primary barrier to molecules penetrating the skin. One approach to overcoming this barrier for the purpose of delivery of active molecules into or via the skin is to employ chemical permeability enhancers, such as dimethylsulfoxide (DMSO). How these molecules exert their effect at the molecular level is not understood. We have investigated the interaction of DMSO with gel-phase bilayers of ceramide 2, the predominant lipid in the stratum corneum, by means of molecular dynamics simulations. The simulations satisfactorily reproduce the phase behavior and the known structural parameters of ceramide 2 bilayers in water. The effect of DMSO on the gel-phase bilayers was investigated at various concentrations over the range 0.0-0.6 mol fraction DMSO. The DMSO molecules accumulate in the headgroup region and weaken the lateral forces between the ceramides. At high concentrations of DMSO (> or =0.4 mol fraction), the ceramide bilayers undergo a phase transition from the gel phase to the liquid crystalline phase. The liquid-crystalline phase of ceramides is expected to be markedly more permeable to solutes than the gel phase. The results are consistent with the experimental evidence that high concentrations of DMSO fluidize the stratum corneum lipids and enhance permeability.
皮肤最外层即角质层的脂质是分子穿透皮肤的主要屏障。为了将活性分子输送到皮肤内或通过皮肤输送活性分子，一种克服这一屏障的方法是使用化学渗透增强剂，如二甲基亚砜（DMSO）。这些分子在分子水平上如何发挥作用尚不清楚。我们通过分子动力学模拟研究了DMSO与神经酰胺2（角质层中的主要脂质）的凝胶相双层膜之间的相互作用。模拟结果令人满意地再现了神经酰胺2双层膜在水中的相行为和已知结构参数。在0.0 - 0.6摩尔分数DMSO范围内的不同浓度下研究了DMSO对凝胶相双层膜的影响。DMSO分子聚集在头基区域，削弱了神经酰胺之间的侧向力。在高浓度DMSO（≥0.4摩尔分数）下，神经酰胺双层膜会经历从凝胶相到液晶相的相变。预计神经酰胺的液晶相比凝胶相对溶质的渗透性明显更高。这些结果与高浓度DMSO使角质层脂质流化并增强渗透性的实验证据一致。
