Department of Physics, Faculty of Science, University of Helsinki, P.O. Box 64, FI-00014 Helsinki, Finland.
Theoretical Physics and Center for Biophysics, Saarland University, 66123 Saarbrücken, Germany.
J Phys Chem B. 2020 Mar 19;124(11):2139-2148. doi: 10.1021/acs.jpcb.9b11005. Epub 2020 Mar 5.
Cholesterol plays a crucial role in modulating the physicochemical properties of biomembranes, both increasing mechanical strength and decreasing permeability. Cholesterol is also a common component of vesicle-based delivery systems, including liposome-based drug delivery systems (LDSs). However, its effect on the partitioning of drug molecules to lipid membranes is very poorly recognized. Herein, we performed a combined experimental/computational study of the potential for the use of the LDS formulation for the delivery of the antifungal drug itraconazole (ITZ). We consider the addition of cholesterol to the lipid membrane. Since ITZ is only weakly soluble in water, its bioavailability is limited. Use of an LDS has thus been proposed. We studied lipid membranes composed of cholesterol, 1-palmitoyl-2-oleoyl--glycerol-3-phosphocholine (POPC), and ITZ using a combination of computational molecular dynamics (MD) simulations of lipid bilayers and Brewster angle microscopy (BAM) experiments of monolayers. Both experimental and computational results show separation of cholesterol and ITZ. Cholesterol has a strong preference to orient parallel to the bilayer normal. However, ITZ, a long and relatively rigid molecule with weakly hydrophilic groups along the backbone, predominantly locates below the interface between the hydrocarbon chain region and the polar region of the membrane, with its backbone oriented parallel to the membrane surface; the orthogonal orientation in the membrane could be the cause of the observed separation. In addition, fluorescence measurements demonstrated that the affinity of ITZ for the lipid membrane is decreased by the presence of cholesterol, which is thus probably not a suitable formulation component of an LDS designed for ITZ delivery.
胆固醇在调节生物膜的物理化学性质方面起着至关重要的作用，既能增加机械强度，又能降低通透性。胆固醇也是基于囊泡的递药系统的常见成分，包括基于脂质体的递药系统（LDS）。然而，其对药物分子分配到脂质膜的影响还没有得到充分认识。在此，我们对基于 LDS 的配方用于递运抗真菌药物伊曲康唑（ITZ）的潜力进行了实验与计算相结合的研究。我们考虑在脂质膜中添加胆固醇。由于 ITZ 在水中的溶解度很低，其生物利用度有限。因此，人们提出了使用 LDS。我们研究了由胆固醇、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱（POPC）和 ITZ 组成的脂质膜，使用脂质双层的计算分子动力学（MD）模拟和单层的布鲁斯特角显微镜（BAM）实验相结合的方法。实验和计算结果都表明胆固醇和 ITZ 发生了分离。胆固醇强烈倾向于平行于双层法向取向。然而，ITZ 是一个长而相对刚性的分子，其主链上只有弱亲水基团，主要位于烃链区和膜极性区之间的界面以下，其主链平行于膜表面；在膜中的正交取向可能是观察到分离的原因。此外，荧光测量表明，胆固醇的存在降低了 ITZ 与脂质膜的亲和力，因此胆固醇可能不是用于 ITZ 递运的 LDS 的合适配方成分。
