Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland.
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089, Warsaw, Poland.
Colloids Surf B Biointerfaces. 2021 Aug;204:111784. doi: 10.1016/j.colsurfb.2021.111784. Epub 2021 Apr 24.
In this work, the effects of simvastatin (SIM), (2-hydroxypropyl)-β-cyclodextrin (HPβCD) and their complex (SIM:HPβCD) on the structure and properties of lipid membranes were investigated for the first time by Langmuir technique combined with PM-IRRAS spectroscopy. An improved understanding of the differences of the interactions between free SIM, and SIM in the form of an inclusion complex with HPβCD with the lipid membrane will improve the development of preparation methods for in vivo applications. Monolayers of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), cholesterol (Chol) and their mixture DMPC:Chol (7:3) served as simple models of one leaflet of the cell membrane. The penetration of well-organized lipid layers by simvastatin lead to their fluidization but the extent of this unwanted effect was smaller when the drug was delivered in the form of the SIM:HPβCD complex. Surface pressure vs. time dependencies showed that the drug encapsulated with cyclodextrin dissociated from the complex upon contact with the lipid layer and the weak interactions between the exterior polar part of the HPβCD and the polar headgroups of the lipid layer facilitated smooth incorporation of the released lipophilic drug into the membrane. At a longer time-scale, the HPβCD ligand released from the complex removed some cholesterol, but not DMPC, from the lipid layer, hence, similarly to the enzyme inhibiting action of statins - it lead to the decrease of the amount of cholesterol in the membrane. Delivery of simvastatin in the form of an inclusion complex with HPβCD is proposed as an approach improving its bioavailability in the cholesterol-lowering therapies.
在这项工作中，首次通过 Langmuir 技术结合 PM-IRRAS 光谱研究了辛伐他汀（SIM）、（2-羟丙基）-β-环糊精（HPβCD）及其复合物（SIM：HPβCD）对脂质膜结构和性质的影响。深入了解游离 SIM 以及以与 HPβCD 形成包合物形式的 SIM 与脂质膜之间相互作用的差异，将有助于开发体内应用的制备方法。1,2-二肉豆蔻酰-sn-甘油-3-磷酸胆碱（DMPC）、胆固醇（Chol）及其混合物 DMPC：Chol（7:3）的单层作为细胞膜单层的简单模型。辛伐他汀有序脂质层的穿透导致其流体化，但当药物以 SIM：HPβCD 复合物的形式给药时，这种不希望的效果程度较小。表面压力与时间的依赖性表明，与脂质层接触时，用环糊精包裹的药物从复合物中解离，并且 HPβCD 的外部极性部分与脂质层的极性头基之间的弱相互作用促进了释放的亲脂性药物顺利掺入膜中。在较长的时间尺度上，从复合物中释放的 HPβCD 配体从脂质层中去除了一些胆固醇，但不包括 DMPC，因此，与他汀类药物的抑制酶作用类似 - 它导致膜中胆固醇的量减少。以与 HPβCD 形成包合物的形式递送辛伐他汀被提议作为提高其在降低胆固醇治疗中的生物利用度的方法。
