桦木酸与不同分子二元系统单分子层的界面相行为研究
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摘要
桦木酸(betulinic acid, BA)是许多植物表皮蜡质的组成成分,与其他蜡质分子共同构成植物与外界环境相互作用的最外层屏障。桦木酸具有多种生物活性,其中抗癌活性是通过直接作用于线粒体膜而引起癌细胞凋亡,抗疟疾活性与其引起的红细胞膜形变有关。桦木酸在植物表皮蜡质中的作用以及对动物线粒体膜、红细胞膜的影响与其单分子层相行为密切相关。本论文从这三方面入手,首次对桦木酸以及桦木酸与不同分子组成的二元系统在空气-水界面上的单分子层相行为进行了系统研究,重点探讨了桦木酸与不同分子间的相互作用以及桦木酸分子结构对这些单分子层相行为的影响。主要内容及结论如下
第一：利用Langmuir单分子层技术,通过表面膜压-面积测量、崩塌情况分析和崩塌前后两次压缩的比较,研究了桦木酸在空气-水界面上的单分子层相行为；通过与硬脂酸、硬脂醇和胆固醇对比以及ChemBio3D Ultra模拟,重点讨论了桦木酸分子结构对其界面相行为的影响和桦木酸分子在空气-水界面上的排布。研究结果表明：在空气-水界面上自由状态下桦木酸分子以极性较大的羧基与超纯水亚相结合,分子倾斜于水面；随单分子层压缩,桦木酸分子在界面上的相行为变化可以分成三个阶段。第一阶段：随表面膜压从0开始增加,不断有桦木酸分子由倾斜取向变成近似竖直取向,以极性较小的羟基指向水面；第二阶段：表面膜压超过约30 mN/m后,越来越多的桦木酸分子转变成近似竖直取向,相邻近似竖直桦木酸分子开始通过羧基间氢键相互结合形成二聚物；第三阶段：当表面膜压超过约48 mN/m时,几乎所有桦木酸分子均取近似竖直取向且以二聚物形式存在。最终表面膜压达到约50 mN/m时桦木酸单分子层崩塌。此外,通过Langmuir-Blodgett (LB)单分子层制备技术将空气-水界面上的桦木酸单分子层转移到云母表面,利用原子力显微镜进行了表面形貌观测。研究结果表明：低表面膜压下桦木酸单分子层存在两种高度不同的区域,对应不同的分子取向；高表面膜压下较高区域多成对出现,可能与近似竖直取向桦木酸分子二聚物的形成有关。
第二：通过表面膜压-面积测量、可混合性分析、热力学稳定性分析以及可压缩性分析,研究了桦木酸分别与植物表皮蜡质成分硬脂酸、硬脂醇组成的二元系统在空气-水界面上的单分子层相行为,重点讨论了不同成分分子间的相互作用和不同桦木酸含量、不同压缩程度下二元系统单分子层结构的变化,对比分析了硬脂酸、硬脂醇不同亲水头基对二元系统单分子层相行为的影响。研究结果表明：(1)在空气-水界面上桦木酸分子与硬脂酸分子、硬脂醇分子均存在相互作用,具有可混合性。桦木酸含量较少、表面膜压较低时,混合单分子层更倾向于凝集,热力学上更趋于稳定,不同成分分子间易于相互吸引,混合单分子层有序性高于对应单一成分单分子层；桦木酸含量较多、表面膜压较高时,混合单分子层更倾向于扩张,更容易出现相分离,不同成分分子间趋于相互排斥,混合单分子层有序性低于单一成分单分子层。因此,少量桦木酸容易插入硬脂酸、硬脂醇区域,相互吸引形成更加有序的结构,低表面膜压下表现更为明显；而硬脂酸、硬脂醇难以插入桦木酸区域,尤其是在高表面膜压下。(2)与桦木酸/硬脂酸混合单分子层相比,桦木酸/硬脂醇混合单分子层有序性增加程度较小,随单分子层压缩进入扩张状态较早、扩张程度较大,相分离和不同成分分子间斥力作用出现较早且程度较大。因此,低表面膜压下桦木酸更易于和亲水头基为羧基的短链饱和脂肪族化合物相互作用,形成较稳定的结构。
第三：通过表面膜压-面积测量、分析以及原子力显微镜观测研究了空气-水界面上桦木酸与线粒体膜特有脂质心磷脂二元系统的单分子层相行为。可混合性分析和ChemBio3D Ultra模拟表明：对桦木酸/心磷脂混合单分子层,表面膜压低于30 mN/m时桦木酸分子倾斜取向和近似竖直取向共存,表面膜压为30 mN/m时桦木酸分子仅取近似竖直倾向;热力学稳定性分析表明：桦木酸/心磷脂混合单分子层中存在相分离和斥力相互作用；可压缩性分析表明：表面膜压30-35 mN/m范围内(对应有生物学意义的生物膜脂质双分子层),20 mol%的桦木酸导致液态压缩相的心磷脂单分子层转变为液态压缩相+液态扩张相共存的桦木酸/心磷脂混合单分子层；原子力显微镜研究表明：表面膜压为30 mN/m时心磷脂分子形成均匀致密的单分子层,20 mol%的桦木酸导致心磷脂区域呈网状结构,随桦木酸含量增加心磷脂区域分子交联程度下降,逐渐变成树枝状结构,不断变细且越来越分散。因此,对应生理条件的较高表面膜压下,在心磷脂单分子层中引入桦木酸,桦木酸分子取近似竖直取向,羟基朝向水面,引起相分离,降低了心磷脂单分子层的有序性,与体内外实验中桦木酸引起的线粒体膜损伤和通透性增加一致。
第四：通过Langmuir单分子层表面膜压-面积测量和分析研究了桦木酸与细胞膜鞘磷脂二元系统在空气-水界面上的单分子层相行为,重点讨论了桦木酸和鞘磷脂之间的相互作用以及不同比例的桦木酸对鞘磷脂单分子层的影响,并从分子结构的角度与胆固醇/鞘磷脂二元系统在界面上的相行为进行了比较。研究结果表明：在空气-水界面上桦木酸分子与鞘磷脂分子具有可混合性,仅桦木酸含量为40 mol%时混合单分子层稳定性略有增加,不同成分分子间存在微弱的引力作用,其他含量下桦木酸分子均引起相分离,不同成分分子相互排斥,且桦木酸占绝大多数时尤为强烈。在对应生理条件的较高表面膜压下,20 mol%的桦木酸导致鞘磷脂单分子层有序性略有降低,桦木酸含量达到40 mol%时鞘磷脂单分子层结构遭到严重破坏。与胆固醇增强鞘磷脂单分子层稳定性和有序性相比,桦木酸更倾向于对鞘磷脂单分子层起破坏作用。
除了对桦木酸以及含桦木酸二元系统界面上的单分子层相行为进行了系统研究,本论文还研究了紫杉醇/DPPC(1,2-Dipalmitoyl-rac-glycero-3-phosphocholine,二棕榈酰磷脂胆碱)二元系统在空气-水界面上的单分子层相行为。紫杉醇透过细胞膜的药物吸收过程及其脂质体制备与紫杉醇/脂质相互作用密切相关,因此,通过Langmuir单分子层表面膜压-面积测量和分析重点研究了紫杉醇与细胞膜脂质DPPC之间的相互作用,并用原子力显微镜对其单分子层微观结构进行了观测。研究结果表明：在空气-水界面上紫杉醇与DPPC相互混合,不同成分分子相互排斥,导致混合单分子中出现相分离,破坏了脂质单分子层的稳定性,证实紫杉醇改变了细胞膜脂质分子的流动性。紫杉醇含量不超过40 mol%时对DPPC单分子层响较小,紫杉醇含量超过40 mol%后DPPC单分子层结构遭到严重破坏。紫杉醇含量为40 mol%时,不同成分分子间混合程度、斥力作用和混合单分子层中相分离程度均远超过其他混合比例,且随单分子层压缩这些现象越来越明显；其他紫杉醇含量下这些现象均随单分子层压缩增强到一定程度后开始减弱。
Betulinic acid (BA) is one of the compositions of various plant cuticular waxes and exhibits multiple biological activities, including anticancer and antimalarial activities. BA can directly induce mitochondrial membrane damage and trigger the mitochondrial pathway of apoptosis in cancer cells. The antimalarial activity of BA has been linked to its ability to cause alteration of erythrocyte membrane shape. The role of BA in plant cuticular waxes and the influence of BA on mammal mitochondrial membrane and erythrocyte membrane are strictly related with the phase behavior of its monolayer. Thus, the phase behaviors of BA monolayer and binary monolayers consisting of BA and different molecules from plant cuticular wax, mammal mitochondrial membrane and erythrocyte membrane have been studied for the first time in this paper. The main points are the interactions between BA and other molecules, and the effects of the structure of BA on the phase behaviors of these monolayers. The details are summarized as follows.
(1) Using Langmuir technique, the phase behavior of BA monolayer has been studied by surface pressure-area (π-A) measurement, collapse analysis and compare of two compression before and after collapse at the air-water interface. The molecular arrangement of BA monolayer and the effect of the structure of BA on the phase behavior have been investigated through contrast with stearic acid (SA), octadecanol (OD) and cholesterol (Chol) and by ChemBio3D Ultra modeling. The results indicate that all BA molecules take tilted orientation with carboxylic group towards water without compression, and that the phase behavior of BA monolayer can be divided into three parts with compression. Part 1:With surface pressure increasing from 0, more and more BA molecules take nearly perpendicular orientation with hydroxyl group towards water instead of tilted orientation. Part 2:With surface pressure increasing from 30 mN/m, the ratio of BA molecules with nearly perpendicular orientation increases continually with BA monolayer compression and carboxylic groups of neighbour nearly perpendicular BA molecules start to be involved in hydrogen bonds to form dimers. Part 3:With surface pressure higher than 48 mN/m, almost all BA molecules take nearly perpendicular orientation and exist in dimers. BA monolayer collapses at about 50 mN/m. Besides, BA monolayer at the air-water interface has been transferred to mica substrates through Langmuir-Blodgett deposition for atomic force microscopy (AFM) observation. The coexistence of two distinct domains with differet thickness at lower surface pressure corresponds to the different orientations of BA molecules. The thicker domains appear in pairs at higher surface pressure might be related with the formation of dimers between neighbour nearly perpendicular BA molecules.
(2) The phase behaviors of BA/SA monolayers and BA/OD monolayers have been studied byπ-A measurement, miscibility analysis, thermodynamic stability analysis and compressibility analysis at the air-water interface. The interactions between BA and SA or OD, and the change of the structure of these binary monolayers with different BA contents and different compression degrees have been emphasized in this research. The influences of the different hydrophilic groups of SA and OD on the phase behaviors of BA/SA monolayers and BA/OD monolayers have been compared. It has been suggested that BA molecules can interact with SA or OD molecules at the air-water interface, and these binary monolayers are miscible. With smaller BA content and at lower surface pressure, different components tend to attract with each other, and the binary monolayers tend to be condensed, more stable thermodynamically, and more ordered. With larger BA content and at higer surface pressure, different components tend to repulse with each other, phase separation occurs, and the binary monolayers tend to be expanded and more disordered. These results indicate that small amount of BA can integrate into SA or OD domains and different components attract with each other to form more ordered structures, especially at lower surface pressure; and that it's hard for SA or OD to be incorporated into BA domains, especially at higher surface pressure. Comparing with BA/SA monolayers, the increase in the ordering of BA/OD monolayers is smaller, and with compression expansion, phase separation and repulsion occur earlier and are more evident in BA/OD monolayers. These results indicate that BA tends to interact with the short-chain saturated aliphatic compound with carboxylic group to form more stable monolayer at lower surface pressure.
(3) The phase behavior of binary monolayers consisting of BA and cardiolipin (CL, a unique phospholipid found only in mitochondrial membrane in mammal) has been studied byπ-A measurement and analyses at the air-water interface and by AFM observation transferred to mica substrates. Miscibility analysis and ChemBio3D Ultra modeling present that in BA/CL monolayers BA takes both tilted and nearly perpendicular orientations at surface pressure below 30 mN/m but only nearly perpendicular orientation at 30 mN/m. Thermodynamic stability analysis indicates that phase separation and repulsion occur in BA/CL monolayers. Compressibility analysis demonstrates that at 30 mN/m,20 mol% BA does markedly translate the liquid-condensed (LC) CL monolayer to BA/CL monolayer with the coexistence of LC and liquid-expanded (LE) phases. AFM observation shows that CL molecules form a homogeneous condensed monolayer at 30 mN/m; that 20 mol% BA leads CL domains to form dense net-like structures; and that CL domains transfer to branch-like structures and the branches become slimmer and thinner with BA content increasing. These results confirm that at high surface pressure corresponding to biologic situation, BA orients nearly perpendicularly, causes phase separation and decreases the ordering of CL monolayer, which is in agreement with the mitochondrial membrane damage and permeabilization induced by BA in vitro and in vivo.
(4) The phase behavior of binary monolayers consisting of BA and sphingomyelin (SM, cell membrane phospholipid) has been studied byπ-A measurement and analyses at the air-water interface using Langmuir technique. The main points are the interaction between BA and SM, and the influence of different BA contents on BA/SM monolayers. The phase behavior of BA/SM monolayers has also been compared with BA/Chol monolayers from the molecular structure perspective. The results indicate that BA/SM monolayers are miscible. Only 40 mol% BA increases the thermodynamic stability of BA/SM monolayers and different conponents attract with each other. With other BA content, phase separation occurs and different components repulse with each other, especially with predominant BA content. At high surface pressure corresponding to biologic situation,20 mol% BA induces a slight decrease of the ordering of SM monolayer, and 40 mol% BA results in serious damage of the structure of SM monolayer. Comparing with the increase in the stability and the ordering of SM monolayer induced by Chol, BA tends to disrupt SM monolayer.
Besides the study of binary monolayers consisiting of BA and different molecules, the phase behavior of binary monolayers consisiting of paclitaxel and dipalmitoyl phosphatidylcholine (DPPC, cell membrane phospholipid) has also been studied at the air-water interface. The absorption of paclitaxel through cell membrane and the preparation of paclitaxel liposome are closely related to the interaction between paclitaxel and lipids. The interaction between paclitaxel and DPPC has been studied byπ-A measurement and analyses using Langmuir technique, and the microstructure of the monolayers has been investigated by AFM observation. The results present that paclitaxel/DPPC monolayers are miscible, phase separation occurs and different components repulse with each other, which is consistent with the disturbance of cell membrane fluidity by paclitaxel. With paclitaxel content no more than 40 mol%, paclitaxel has a little influence on DPPC monolayer; more than 40 mol% paclitaxel results in disruption of the structure of DPPC monolayer. With 40 mol% paclitaxel, miscibility, phase separation and repulsion are most apparent and increase with monolayer compression. With other paclitaxel content, all these states increase at first and then decrease with monolayer compression.
第一：利用Langmuir单分子层技术,通过表面膜压-面积测量、崩塌情况分析和崩塌前后两次压缩的比较,研究了桦木酸在空气-水界面上的单分子层相行为；通过与硬脂酸、硬脂醇和胆固醇对比以及ChemBio3D Ultra模拟,重点讨论了桦木酸分子结构对其界面相行为的影响和桦木酸分子在空气-水界面上的排布。研究结果表明：在空气-水界面上自由状态下桦木酸分子以极性较大的羧基与超纯水亚相结合,分子倾斜于水面；随单分子层压缩,桦木酸分子在界面上的相行为变化可以分成三个阶段。第一阶段：随表面膜压从0开始增加,不断有桦木酸分子由倾斜取向变成近似竖直取向,以极性较小的羟基指向水面；第二阶段：表面膜压超过约30 mN/m后,越来越多的桦木酸分子转变成近似竖直取向,相邻近似竖直桦木酸分子开始通过羧基间氢键相互结合形成二聚物；第三阶段：当表面膜压超过约48 mN/m时,几乎所有桦木酸分子均取近似竖直取向且以二聚物形式存在。最终表面膜压达到约50 mN/m时桦木酸单分子层崩塌。此外,通过Langmuir-Blodgett (LB)单分子层制备技术将空气-水界面上的桦木酸单分子层转移到云母表面,利用原子力显微镜进行了表面形貌观测。研究结果表明：低表面膜压下桦木酸单分子层存在两种高度不同的区域,对应不同的分子取向；高表面膜压下较高区域多成对出现,可能与近似竖直取向桦木酸分子二聚物的形成有关。
第二：通过表面膜压-面积测量、可混合性分析、热力学稳定性分析以及可压缩性分析,研究了桦木酸分别与植物表皮蜡质成分硬脂酸、硬脂醇组成的二元系统在空气-水界面上的单分子层相行为,重点讨论了不同成分分子间的相互作用和不同桦木酸含量、不同压缩程度下二元系统单分子层结构的变化,对比分析了硬脂酸、硬脂醇不同亲水头基对二元系统单分子层相行为的影响。研究结果表明：(1)在空气-水界面上桦木酸分子与硬脂酸分子、硬脂醇分子均存在相互作用,具有可混合性。桦木酸含量较少、表面膜压较低时,混合单分子层更倾向于凝集,热力学上更趋于稳定,不同成分分子间易于相互吸引,混合单分子层有序性高于对应单一成分单分子层；桦木酸含量较多、表面膜压较高时,混合单分子层更倾向于扩张,更容易出现相分离,不同成分分子间趋于相互排斥,混合单分子层有序性低于单一成分单分子层。因此,少量桦木酸容易插入硬脂酸、硬脂醇区域,相互吸引形成更加有序的结构,低表面膜压下表现更为明显；而硬脂酸、硬脂醇难以插入桦木酸区域,尤其是在高表面膜压下。(2)与桦木酸/硬脂酸混合单分子层相比,桦木酸/硬脂醇混合单分子层有序性增加程度较小,随单分子层压缩进入扩张状态较早、扩张程度较大,相分离和不同成分分子间斥力作用出现较早且程度较大。因此,低表面膜压下桦木酸更易于和亲水头基为羧基的短链饱和脂肪族化合物相互作用,形成较稳定的结构。
第三：通过表面膜压-面积测量、分析以及原子力显微镜观测研究了空气-水界面上桦木酸与线粒体膜特有脂质心磷脂二元系统的单分子层相行为。可混合性分析和ChemBio3D Ultra模拟表明：对桦木酸/心磷脂混合单分子层,表面膜压低于30 mN/m时桦木酸分子倾斜取向和近似竖直取向共存,表面膜压为30 mN/m时桦木酸分子仅取近似竖直倾向;热力学稳定性分析表明：桦木酸/心磷脂混合单分子层中存在相分离和斥力相互作用；可压缩性分析表明：表面膜压30-35 mN/m范围内(对应有生物学意义的生物膜脂质双分子层),20 mol%的桦木酸导致液态压缩相的心磷脂单分子层转变为液态压缩相+液态扩张相共存的桦木酸/心磷脂混合单分子层；原子力显微镜研究表明：表面膜压为30 mN/m时心磷脂分子形成均匀致密的单分子层,20 mol%的桦木酸导致心磷脂区域呈网状结构,随桦木酸含量增加心磷脂区域分子交联程度下降,逐渐变成树枝状结构,不断变细且越来越分散。因此,对应生理条件的较高表面膜压下,在心磷脂单分子层中引入桦木酸,桦木酸分子取近似竖直取向,羟基朝向水面,引起相分离,降低了心磷脂单分子层的有序性,与体内外实验中桦木酸引起的线粒体膜损伤和通透性增加一致。
第四：通过Langmuir单分子层表面膜压-面积测量和分析研究了桦木酸与细胞膜鞘磷脂二元系统在空气-水界面上的单分子层相行为,重点讨论了桦木酸和鞘磷脂之间的相互作用以及不同比例的桦木酸对鞘磷脂单分子层的影响,并从分子结构的角度与胆固醇/鞘磷脂二元系统在界面上的相行为进行了比较。研究结果表明：在空气-水界面上桦木酸分子与鞘磷脂分子具有可混合性,仅桦木酸含量为40 mol%时混合单分子层稳定性略有增加,不同成分分子间存在微弱的引力作用,其他含量下桦木酸分子均引起相分离,不同成分分子相互排斥,且桦木酸占绝大多数时尤为强烈。在对应生理条件的较高表面膜压下,20 mol%的桦木酸导致鞘磷脂单分子层有序性略有降低,桦木酸含量达到40 mol%时鞘磷脂单分子层结构遭到严重破坏。与胆固醇增强鞘磷脂单分子层稳定性和有序性相比,桦木酸更倾向于对鞘磷脂单分子层起破坏作用。
除了对桦木酸以及含桦木酸二元系统界面上的单分子层相行为进行了系统研究,本论文还研究了紫杉醇/DPPC(1,2-Dipalmitoyl-rac-glycero-3-phosphocholine,二棕榈酰磷脂胆碱)二元系统在空气-水界面上的单分子层相行为。紫杉醇透过细胞膜的药物吸收过程及其脂质体制备与紫杉醇/脂质相互作用密切相关,因此,通过Langmuir单分子层表面膜压-面积测量和分析重点研究了紫杉醇与细胞膜脂质DPPC之间的相互作用,并用原子力显微镜对其单分子层微观结构进行了观测。研究结果表明：在空气-水界面上紫杉醇与DPPC相互混合,不同成分分子相互排斥,导致混合单分子中出现相分离,破坏了脂质单分子层的稳定性,证实紫杉醇改变了细胞膜脂质分子的流动性。紫杉醇含量不超过40 mol%时对DPPC单分子层响较小,紫杉醇含量超过40 mol%后DPPC单分子层结构遭到严重破坏。紫杉醇含量为40 mol%时,不同成分分子间混合程度、斥力作用和混合单分子层中相分离程度均远超过其他混合比例,且随单分子层压缩这些现象越来越明显；其他紫杉醇含量下这些现象均随单分子层压缩增强到一定程度后开始减弱。
Betulinic acid (BA) is one of the compositions of various plant cuticular waxes and exhibits multiple biological activities, including anticancer and antimalarial activities. BA can directly induce mitochondrial membrane damage and trigger the mitochondrial pathway of apoptosis in cancer cells. The antimalarial activity of BA has been linked to its ability to cause alteration of erythrocyte membrane shape. The role of BA in plant cuticular waxes and the influence of BA on mammal mitochondrial membrane and erythrocyte membrane are strictly related with the phase behavior of its monolayer. Thus, the phase behaviors of BA monolayer and binary monolayers consisting of BA and different molecules from plant cuticular wax, mammal mitochondrial membrane and erythrocyte membrane have been studied for the first time in this paper. The main points are the interactions between BA and other molecules, and the effects of the structure of BA on the phase behaviors of these monolayers. The details are summarized as follows.
(1) Using Langmuir technique, the phase behavior of BA monolayer has been studied by surface pressure-area (π-A) measurement, collapse analysis and compare of two compression before and after collapse at the air-water interface. The molecular arrangement of BA monolayer and the effect of the structure of BA on the phase behavior have been investigated through contrast with stearic acid (SA), octadecanol (OD) and cholesterol (Chol) and by ChemBio3D Ultra modeling. The results indicate that all BA molecules take tilted orientation with carboxylic group towards water without compression, and that the phase behavior of BA monolayer can be divided into three parts with compression. Part 1:With surface pressure increasing from 0, more and more BA molecules take nearly perpendicular orientation with hydroxyl group towards water instead of tilted orientation. Part 2:With surface pressure increasing from 30 mN/m, the ratio of BA molecules with nearly perpendicular orientation increases continually with BA monolayer compression and carboxylic groups of neighbour nearly perpendicular BA molecules start to be involved in hydrogen bonds to form dimers. Part 3:With surface pressure higher than 48 mN/m, almost all BA molecules take nearly perpendicular orientation and exist in dimers. BA monolayer collapses at about 50 mN/m. Besides, BA monolayer at the air-water interface has been transferred to mica substrates through Langmuir-Blodgett deposition for atomic force microscopy (AFM) observation. The coexistence of two distinct domains with differet thickness at lower surface pressure corresponds to the different orientations of BA molecules. The thicker domains appear in pairs at higher surface pressure might be related with the formation of dimers between neighbour nearly perpendicular BA molecules.
(2) The phase behaviors of BA/SA monolayers and BA/OD monolayers have been studied byπ-A measurement, miscibility analysis, thermodynamic stability analysis and compressibility analysis at the air-water interface. The interactions between BA and SA or OD, and the change of the structure of these binary monolayers with different BA contents and different compression degrees have been emphasized in this research. The influences of the different hydrophilic groups of SA and OD on the phase behaviors of BA/SA monolayers and BA/OD monolayers have been compared. It has been suggested that BA molecules can interact with SA or OD molecules at the air-water interface, and these binary monolayers are miscible. With smaller BA content and at lower surface pressure, different components tend to attract with each other, and the binary monolayers tend to be condensed, more stable thermodynamically, and more ordered. With larger BA content and at higer surface pressure, different components tend to repulse with each other, phase separation occurs, and the binary monolayers tend to be expanded and more disordered. These results indicate that small amount of BA can integrate into SA or OD domains and different components attract with each other to form more ordered structures, especially at lower surface pressure; and that it's hard for SA or OD to be incorporated into BA domains, especially at higher surface pressure. Comparing with BA/SA monolayers, the increase in the ordering of BA/OD monolayers is smaller, and with compression expansion, phase separation and repulsion occur earlier and are more evident in BA/OD monolayers. These results indicate that BA tends to interact with the short-chain saturated aliphatic compound with carboxylic group to form more stable monolayer at lower surface pressure.
(3) The phase behavior of binary monolayers consisting of BA and cardiolipin (CL, a unique phospholipid found only in mitochondrial membrane in mammal) has been studied byπ-A measurement and analyses at the air-water interface and by AFM observation transferred to mica substrates. Miscibility analysis and ChemBio3D Ultra modeling present that in BA/CL monolayers BA takes both tilted and nearly perpendicular orientations at surface pressure below 30 mN/m but only nearly perpendicular orientation at 30 mN/m. Thermodynamic stability analysis indicates that phase separation and repulsion occur in BA/CL monolayers. Compressibility analysis demonstrates that at 30 mN/m,20 mol% BA does markedly translate the liquid-condensed (LC) CL monolayer to BA/CL monolayer with the coexistence of LC and liquid-expanded (LE) phases. AFM observation shows that CL molecules form a homogeneous condensed monolayer at 30 mN/m; that 20 mol% BA leads CL domains to form dense net-like structures; and that CL domains transfer to branch-like structures and the branches become slimmer and thinner with BA content increasing. These results confirm that at high surface pressure corresponding to biologic situation, BA orients nearly perpendicularly, causes phase separation and decreases the ordering of CL monolayer, which is in agreement with the mitochondrial membrane damage and permeabilization induced by BA in vitro and in vivo.
(4) The phase behavior of binary monolayers consisting of BA and sphingomyelin (SM, cell membrane phospholipid) has been studied byπ-A measurement and analyses at the air-water interface using Langmuir technique. The main points are the interaction between BA and SM, and the influence of different BA contents on BA/SM monolayers. The phase behavior of BA/SM monolayers has also been compared with BA/Chol monolayers from the molecular structure perspective. The results indicate that BA/SM monolayers are miscible. Only 40 mol% BA increases the thermodynamic stability of BA/SM monolayers and different conponents attract with each other. With other BA content, phase separation occurs and different components repulse with each other, especially with predominant BA content. At high surface pressure corresponding to biologic situation,20 mol% BA induces a slight decrease of the ordering of SM monolayer, and 40 mol% BA results in serious damage of the structure of SM monolayer. Comparing with the increase in the stability and the ordering of SM monolayer induced by Chol, BA tends to disrupt SM monolayer.
Besides the study of binary monolayers consisiting of BA and different molecules, the phase behavior of binary monolayers consisiting of paclitaxel and dipalmitoyl phosphatidylcholine (DPPC, cell membrane phospholipid) has also been studied at the air-water interface. The absorption of paclitaxel through cell membrane and the preparation of paclitaxel liposome are closely related to the interaction between paclitaxel and lipids. The interaction between paclitaxel and DPPC has been studied byπ-A measurement and analyses using Langmuir technique, and the microstructure of the monolayers has been investigated by AFM observation. The results present that paclitaxel/DPPC monolayers are miscible, phase separation occurs and different components repulse with each other, which is consistent with the disturbance of cell membrane fluidity by paclitaxel. With paclitaxel content no more than 40 mol%, paclitaxel has a little influence on DPPC monolayer; more than 40 mol% paclitaxel results in disruption of the structure of DPPC monolayer. With 40 mol% paclitaxel, miscibility, phase separation and repulsion are most apparent and increase with monolayer compression. With other paclitaxel content, all these states increase at first and then decrease with monolayer compression.
引文
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