Dzieciuch Monika, Rissanen Sami, Szydłowska Natalia, Bunker Alex, Kumorek Marta, Jamróz Dorota, Vattulainen Ilpo, Nowakowska Maria, Róg Tomasz, Kepczynski Mariusz
†Faculty of Chemistry, Jagiellonian University, Krakow 31-007, Poland.
‡Department of Physics, Tampere University of Technology, Tampere 33720, Finland.
J Phys Chem B. 2015 Jun 4;119(22):6646-57. doi: 10.1021/acs.jpcb.5b01351. Epub 2015 May 22.
Sterically stabilized liposomes (SSLs) (PEGylated liposomes) are applied as effective drug delivery vehicles. Understanding the interactions between hydrophobic compounds and PEGylated membranes is therefore important to determine the effectiveness of PEGylated liposomes for delivery of drugs or other bioactive substances. In this study, we have combined fluorescence quenching analysis (FQA) experiments and all-atom molecular dynamics (MD) simulations to study the effect of membrane PEGylation on the location and orientation of 5,10,15,20-tetrakis(4-hydroxyphenyl)porphyrin (p-THPP) that has been used in our study as a model hydrophobic compound. First, we consider the properties of p-THPP in the presence of different fluid phosphatidylcholine bilayers that we use as model systems for protein-free cell membranes. Next, we studied the interaction between PEGylated membranes and p-THPP. Our MD simulation results indicated that the arrangement of p-THPP within zwitterionic membranes is dependent on their free volume, and p-THPP solubilized in PEGylated liposomes is localized in two preferred positions: deep within the membrane (close to the center of the bilayer) and in the outer PEG corona (p-THPP molecules being wrapped with the polymer chains). Fluorescence quenching methods confirmed the results of atomistic MD simulations and showed two populations of p-THPP molecules as in MD simulations. Our results provide both an explanation for the experimental observation that PEGylation improves the drug-loading efficiency of membranes and also a more detailed molecular-level description of the interactions between porphyrins and lipid membranes.
空间稳定脂质体（SSLs）（聚乙二醇化脂质体）被用作有效的药物递送载体。因此，了解疏水化合物与聚乙二醇化膜之间的相互作用对于确定聚乙二醇化脂质体递送药物或其他生物活性物质的有效性至关重要。在本研究中，我们结合了荧光猝灭分析（FQA）实验和全原子分子动力学（MD）模拟，以研究膜聚乙二醇化对5,10,15,20-四（4-羟苯基）卟啉（p-THPP）的位置和取向的影响，p-THPP在我们的研究中用作模型疏水化合物。首先，我们考虑了p-THPP在不同流体磷脂酰胆碱双层存在下的性质，我们将其用作无蛋白细胞膜的模型系统。接下来，我们研究了聚乙二醇化膜与p-THPP之间的相互作用。我们的MD模拟结果表明，p-THPP在两性离子膜内的排列取决于它们的自由体积，并且溶解在聚乙二醇化脂质体中的p-THPP定位在两个优选位置：膜的深处（靠近双层的中心）和外部聚乙二醇冠层（p-THPP分子被聚合物链包裹）。荧光猝灭方法证实了原子MD模拟的结果，并显示出与MD模拟中一样的两种p-THPP分子群体。我们的结果既为聚乙二醇化提高膜的药物负载效率这一实验观察结果提供了解释，也对卟啉与脂质膜之间的相互作用进行了更详细的分子水平描述。
