Le-Deygen Irina M, Skuredina Anna A, Safronova Anastasia S, Yakimov Ivan D, Kolmogorov Ilya M, Deygen Daria M, Burova Tatiana V, Grinberg Natalia V, Grinberg Valery Y, Kudryashova Elena V
Lomonosov MSU, Faculty of Chemistry, Chemical Enzymology Department, 119991, Moscow, Leninskie Gory, 1, 3, Russia.
Lomonosov MSU, Faculty of Chemistry, Chemical Enzymology Department, 119991, Moscow, Leninskie Gory, 1, 3, Russia.
Chem Phys Lipids. 2020 May;228:104891. doi: 10.1016/j.chemphyslip.2020.104891. Epub 2020 Feb 10.
Most drugs besides their intended activity, express undesired side effects, including those with the engagement of cell membrane. Previously, such undesired nonspecific effects on the membrane have been shown for a number of widely used nonsteroidal anti-inflammatory drugs. In this paper, we study the mechanism of interaction between moxifloxacin (Mox), antibacterial drug of broad specificity, with lipid bilayer of the liposomes of various compositions as a model of cell membrane using a combination of spectroscopy methods, including ATR-FTIR spectroscopy, circular dichroism, UV and fluorescence spectroscopy. The fine structure of the moxifloxacin-liposome complex, localization of the drug in bilayer and the main sites of Mox interaction with lipid membrane were determined. Lipid composition of the liposome plays a key role in the interaction with moxifloxacin, drastically affecting the loading efficiency, strength and character of drug binding, lipid phase segregation and phase transition parameters. In case of anionic liposomes composed of dipalmitoylphosphatidylcholine (DPPC) and cardiolipin (CL) the electrostatic interaction of negatively charged nitrogen in heterocycle moiety of moxifloxacin with cardiolipin phosphate groups is a crucial factor for stable complex formation. The study of moxifloxacin-liposome complex behavior at phase transition in bilayer by DSC method revealed that in DPPC/CL liposomes system two microphases with different content of CL coexist and Mox interacts with both of these microphases resulting in the formation of two types of complexes with different structure and phase transition temperature. This binding stabilized the gel-state of the lipid bilayer with increasing the phase transition temperature Tm up to 3-5 °C. A different situation is observed for neutral DPPC liposomes: drug interaction with bilayer results in defects formation and a fluidization effect in lipid bilayer, resulted to decrease the Tm value by 2-4 °C. Moxifloxacin is not firmly binding in the membrane of DPPC and drug releases rapidly.
大多数药物除了具有预期的活性外，还会表现出不良副作用，包括那些涉及细胞膜的副作用。此前，已证明许多广泛使用的非甾体抗炎药对膜有这种不良的非特异性作用。在本文中，我们使用包括衰减全反射傅里叶变换红外光谱（ATR-FTIR光谱）、圆二色性、紫外和荧光光谱在内的多种光谱方法，研究了广谱抗菌药物莫西沙星（Mox）与各种组成的脂质体脂质双层之间的相互作用机制，该脂质体作为细胞膜模型。确定了莫西沙星-脂质体复合物的精细结构、药物在双层中的定位以及莫西沙星与脂质膜相互作用的主要位点。脂质体的脂质组成在与莫西沙星的相互作用中起关键作用，极大地影响药物的负载效率、结合强度和性质、脂质相分离以及相变参数。对于由二棕榈酰磷脂酰胆碱（DPPC）和心磷脂（CL）组成的阴离子脂质体，莫西沙星杂环部分带负电荷的氮与心磷脂磷酸基团的静电相互作用是形成稳定复合物的关键因素。通过差示扫描量热法（DSC）研究双层相变过程中莫西沙星-脂质体复合物的行为表明；在DPPC/CL脂质体系统中，存在两种CL含量不同的微相，莫西沙星与这两种微相都相互作用，导致形成两种结构和相变温度不同的复合物。这种结合使脂质双层的凝胶态稳定，相变温度Tm升高3至5℃。对于中性DPPC脂质体则观察到不同的情况：药物与双层的相互作用导致脂质双层中形成缺陷和流化效应，使Tm值降低2至4℃。莫西沙星在DPPC膜中结合不牢固，药物释放迅速。
