Glycerol Solvates DPPC Headgroups and Localizes in the Interfacial Regions of Model Pulmonary Interfaces Altering Bilayer Structure.
Glycerol Solvates DPPC Headgroups and Localizes in the Interfacial Regions of Model Pulmonary Interfaces Altering Bilayer Structure.
复制标题
甘油溶解 DPPC 头基并定位于改变双层结构的模型肺界面的界面区域。
DOI：
10.1021/acs.langmuir.8b00866
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Terakosolphan W
中科院分区：
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作者：
Terakosolphan W
在肺部给药制剂中加入甘油可能会通过延缓吸入性类固醇在肺上皮细胞的转运而影响其生物利用度。本研究的目的是评价甘油与模拟肺界面的分子相互作用是否为甘油修饰吸入性药物转运提供了生物物理基础。以二棕榈酰磷脂酰胆碱(DPPC)单层和脂质体为模型肺界面，通过互补生物物理测量和分子动力学(MD)模拟，考察了原装甘油(0-30%w/w)对其结构和动力学的影响。甘油优先与DPPC界面区域的羰基以及头基上的磷酸盐和胆碱相互作用，从而导致头基溶剂化壳的尺寸增加，这在Langmuir等温线和MD模拟中都可以看到DPPC单分子层和双分子层的膨胀(分子面积从52增加到68ä2)。小角中子散射和分子动力学模拟都表明，在30%w/w甘油中，∼3ä可使凝胶相DPPC双层厚度减小，这一现象与从傅立叶变换红外光谱数据中观察到的现象一致，即甘油使脂头基团保持平行于膜平面的取向，而不是在纯水中采用更垂直的构象。此外，FTIR测量表明，在甘油存在下，DPPC酰链的末端甲基被限制。这一观察结果得到了MD模拟的支持，该模拟预测了甘油在相邻的DPPC头基之间的桥联可能是其膜硬化效应的一个来源。总之，这些数据表明，甘油优先溶解DPPC头基，并定位于界面区域的特定区域，导致DPPC双层结构的变化，这可能会影响细胞对药物的通透性。
The inclusion of glycerol in formulations for pulmonary drug delivery may affect the bioavailability of inhaled steroids by retarding their transport across the lung epithelium. The aim of this study was to evaluate whether the molecular interactions of glycerol with model pulmonary interfaces provide a biophysical basis for glycerol modifying inhaled drug transport. Dipalmitoylphosphatidylcholine (DPPC) monolayers and liposomes were used as model pulmonary interfaces, in order to examine the effects of bulk glycerol (0–30% w/w) on their structures and dynamics using complementary biophysical measurements and molecular dynamics (MD) simulations. Glycerol was found to preferentially interact with the carbonyl groups in the interfacial region of DPPC and with phosphate and choline in the headgroup, thus causing an increase in the size of the headgroup solvation shell, as evidenced by an expansion of DPPC monolayers (molecular area increased from 52 to 68 Å2) and bilayers seen in both Langmuir isotherms and MD simulations. Both small angle neutron scattering and MD simulations indicated a reduction in gel phase DPPC bilayer thickness by ∼3 Å in 30% w/w glycerol, a phenomenon consistent with the observation from FTIR data, that glycerol caused the lipid headgroup to remain oriented parallel to the membrane plane in contrast to its more perpendicular conformation adopted in pure water. Furthermore, FTIR measurements suggested that the terminal methyl groups of the DPPC acyl chains were constrained in the presence of glycerol. This observation is supported by MD simulations, which predict bridging between adjacent DPPC headgroups by glycerol as a possible source of its putative membrane stiffening effect. Collectively, these data indicate that glycerol preferentially solvates DPPC headgroups and localizes in specific areas of the interfacial region, resulting in structural changes to DPPC bilayers which may influence cell permeability to drugs.