表面活性剂囊泡与含类固醇结构的两亲分子的相互作用

发布时间：2018-05-07 04:35

本文选题：热力学 + 胆汁酸盐　；参考：《河南师范大学》2017年硕士论文

【摘要】：表面活性剂聚集体对于药物具有缓释或定向释放功能,是极具特色的仿生药物载体。因此对于聚集体的组成、稳定性、微结构调控研究具有重要意义。本论文通过两种以上混合的表面活性剂构建双亲分子聚集体(胶束,囊泡),利用热力学研究的主要手段?等温滴定量热(ITC)和差式扫描量热(DSC)与荧光、浊度以及低温透射电镜(cryo-TEM)方法相结合,研究双亲分子聚集体与脱氧胆酸钠(Na DCA)、胆酸钠(Na CA)及含类固醇结构的改性葡聚糖的分子间相互作用的热力学及聚集行为。详细讨论了双亲分子疏水侧链、表面活性剂的极性头(化学官能团及电荷)、溶液的组成及浓度等因素,对由两种或两种以上表面活性剂构成的复杂体系分子聚集过程的影响,讨论了双亲分子间的协同作用,分析了阳离子季按盐型gemini(C_(12)C_SC_(12)Br_2,S=3,10)表面活性剂的间隔基团(spacer)在相反电荷的表面活性剂混合囊泡聚集过程中的作用。结合这些复杂混合体系的热力学性质,研究了聚合物侧链胆汁酸基团及骨架对囊泡聚集形态的影响。研究内容和结果如下:1. 相反电荷的两种双亲分子体系——C_(12)C_SC_(12)Br_2/Na DCA与对于gemini/Na DCA混合体系,利用稳态荧光探针法测定了混合体系C_(12)C_SC_(12)Br_2(S=2,6,10)/Na DCA的临界胶束浓度(cmc_(mix))。用ITC方法测定了在C_(12)C_6C_(12)Br_2与Na DCA相互作用过程中各种相变发生的临界浓度(C_P,C_R,C_M)及相应的焓变。将这些参数与C_(12)C_SC_(12)Br_2/Na CA的混合体系比较,由于胆汁酸盐结构的不同,C_(12)C_SC_(12)Br_2/Na DCA比C_(12)C_SC_(12)Br_2/Na CA有更宽的液晶相组成区间。对于C_(12)C_6C_(12)Br_2/Dex-15CACOONa混合体系,从其相互作用的观测焓(ΔH_(obs))和浊度(OD)随gemini的浓度(C_(gemini))变化曲线得到了相反电荷体系各种相变的临界浓度和焓变化。通过Cryo-TEM观测了各相中聚集体的形态。由于gemini表面活性剂双极性头和双疏水链的存在,使gemini可以用作分子交联剂,在远远小于等电荷比的gemini浓度下使由Dex-15CACOONa侧链形成的聚集体之间发生交联,此时游离的gemini浓度几乎为零,聚集体带负电荷。通过分析C_(12)C_6C_(12)Br_2/Dex-15CACOONa相互作用中涉及的各种因素(两亲分子的类型,聚电解质的构象,嫁接基团的性质)推测混合聚集体形成的驱动力,并提出了相互作用的热力学模型。2.三种双亲分子Na DCA/DDAB/SDS和Dex-3DCA/DDAB/SDS的混合体系制备了阴阳离子表面活性剂混合囊泡(DDAB/SDS(x _(SDS)=0.6)),通过ITC方法测定了Na DCA与DDAB/SDS混合囊泡的相互作用焓变化,并用Cryo-TEM表征了混合囊泡的多分散性。发现混合囊泡的形态和尺寸依赖于Na DCA的摩尔分数。进一步通过DSC方法测定了Na DCA/DDAB/SDS混合体系的凝胶到液晶的相变温度(T_m),发现Na DCA的加入降低了DDAB/SDS混合囊泡的T_m,表明Na DCA在调控混合囊泡尺寸和形态的同时使囊泡的稳定性降低。对于Dex-3DCA/DDAB/SDS混合体系,由于葡聚糖骨架的限制,Dex-3DCA对DDAB/SDS混合囊泡的调控不同于上述包含自由的Na DCA的情况。侧链(-DCA)插入到混合囊泡双层中,同时聚合物链包裹在囊泡外表面,导致囊泡的大小和形状发生变化,凝胶向液晶的相转变温度(T_m)增大,因此Dex-3DCA能够提高DDAB/SDS混合囊泡的稳定性。3.三种双亲分子Na DCA/C_(12)C_SC_(12)Br_2/SDS和Dex-3DCA/C_(12)C_SC_(12)Br_2/SDS的混合体系选取C_(12)C_3C_(12)Br_2/SDS与C_(12)C_(10)C_(12)Br_2/SDS两种混合体系制备囊泡,研究了gemini的间隔基团(spacer)对混合囊泡形态的影响。C_(12)C_3C_(12)Br_2/SDS体系形成小的球形囊泡,而对于gemini的间隔基团烷基链较长的C_(12)C_(10)C_(12)Br_2/SDS体系形成大的多层多核囊泡。Na DCA可以调控C_(12)C_3C_(12)Br_2/SDS混合囊泡从球形囊泡到椭球型囊泡的转变,脱氧胆酸改性的聚合物(Dex-3DCA)可以调控C_(12)C_3C_(12)Br_2/SDS混合囊泡从球形囊泡到棒状聚集体的转变。对于C_(12)C_(10)C_(12)Br_2/SDS体系,Dex-3DCA能够调节C_(12)C_(10)C_(12)Br_2/SDS聚集体的形状与大小,而游离的Na DCA能够溶解囊泡膜,改变多层、多核囊泡的层数。这些结果对于进一步深入扩展此类复杂体系的理论与应用研究有着重要的指导意义。生物相容性的胆汁酸盐及含类固醇结构的改性聚合物对囊泡聚集体的功能化调控在药物的包埋和释放方面的研究具有重要的理论和实际意义。
[Abstract]:The surfactant polymer is a highly characteristic biomimetic drug carrier for drug release or directional release. Therefore, it is of great significance for the study of the composition, stability and microstructural regulation of the aggregates. In this paper, the construction of amphiphilic polymer aggregates (micelles, vesicles) by more than two kinds of mixed surfactants is used in this paper, and thermodynamics is used. The main means of the study, isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC), were combined with fluorescence, turbidity and low temperature transmission electron microscopy (cryo-TEM) to study the thermodynamics and aggregation behavior of the intermolecular interaction of amphiphilic molecule aggregates and sodium deoxycholate (Na DCA), sodium cholate (Na CA) and modified glucan containing steroid structure. The hydrophobic side chain of the parent molecules, the polar head (chemical functional group and charge) of surfactant, the composition and concentration of the solution, and the influence on the molecular aggregation process of complex systems composed of two or more than two kinds of surfactants were discussed in detail. The synergistic action between the two parent molecules was discussed, and the cationic season was analyzed by the salt type Gemini (C_). 12) the effect of the spacer group (spacer) of C_SC_ (12) Br_2, S=3,10 on the aggregation of the mixed vesicles of the surface active agent of the opposite charge. The effects of the bile acid group and skeleton on the morphology of the vesicles in the polymer side chain are studied. The contents and results are as follows: 1. the contrary is the contrary. The two parent molecular systems of charge - C_ (12) C_SC_ (12) Br_2/Na DCA and the mixed system of gemini/Na DCA have been used to determine the critical micelle concentration of C_ (12) C_SC_ (12) Br_2 (S=2,6,10) /Na DCA by the steady-state fluorescence probe method. The critical concentration of change (C_P, C_R, C_M) and corresponding enthalpy change. Comparing these parameters with the mixture of C_ (12) C_SC_ (12) Br_2/Na CA, C_ (12) C_SC_ (12) Br_2/Na DCA has a wider range of liquid crystal phase than C_ (12) because of the structure of bile salts. The observation enthalpy (delta H_ (OBS)) and turbidity (OD) of the interaction with the concentration of Gemini (C_ (Gemini)) obtained the critical concentration and enthalpy change of the various phase transitions in the opposite charge system. The morphology of the aggregates in each phase was observed by Cryo-TEM. The Gemini can be used as a fraction because of the existence of the bipolar head and the double hydrophobic chain of the gemini surface active agent. Sub crosslinker, crosslinked by a Gemini concentration of Dex-15CACOONa side chain at a concentration of Gemini far less than the equal charge ratio, when the free Gemini concentration is almost zero and the aggregate is negatively charged. By analyzing the various factors involved in the interaction of C_ (12) C_6C_ (12) Br_2/Dex-15CACOONa (two parent molecules, polyelectrolytes) Conformation of the conformation, the properties of the graft group) speculates the driving force of the formation of the mixed aggregates, and proposes a thermodynamic model for interaction between three parent molecules, Na DCA/DDAB/SDS and Dex-3DCA/DDAB/SDS, to prepare the mixed vesicles (DDAB/SDS (x) =0.6) of the Yin and Yang surfactant (DDAB/SDS (SDS) =0.6), and the Na DCA and DDAB/SDS are measured by the ITC method. The interaction enthalpy of the mixed vesicles is changed and the polydispersity of the mixed vesicles is characterized by Cryo-TEM. It is found that the morphology and size of the mixed vesicles depend on the mole fraction of the Na DCA. The phase transition temperature (T_m) of the Na DCA/DDAB/SDS mixture gel to the liquid crystal (T_m) is further determined by the DSC method. It is found that the addition of Na DCA reduces the mixing of DDAB/SDS. The T_m of the vesicle indicates that Na DCA reduces the stability of the vesicles while regulating the size and morphology of the mixed vesicles. For the Dex-3DCA/DDAB/SDS mixed system, the regulation of DDAB/SDS mixed vesicles by Dex-3DCA is different from that of the free Na DCA. The side chain (-DCA) is inserted into the mixed vesicle double layer. When the polymer chain is wrapped on the outer surface of the vesicle, the size and shape of the vesicles are changed, the phase transition temperature of the gel is increased to the liquid crystal (T_m), so Dex-3DCA can improve the stability of the DDAB/SDS mixed vesicles, and the mixed system of.3. three parent molecules Na DCA/C_ (12) C_SC_ (12) Br_2/SDS and Dex-3DCA/C_ (12) C_SC_ (12) Br_2/SDS is selected for C_ (12). C_3C_ (12) Br_2/SDS and C_ (12) C_ (10) C_ (12) Br_2/SDS were used to prepare the vesicles. The effect of the Gemini spacer group (spacer) on the morphology of the mixed vesicles was studied. The.C_ (12) C_3C_ (12) Br_2/SDS system formed a small spherical vesicle, and a large multilayer for the longer alkyl chain (12) of the septum group (10) (12) of Gemini was formed. .Na DCA can regulate the transformation of C_ (12) C_3C_ (12) Br_2/SDS mixed vesicles from spherical vesicles to ellipsoidal vesicles. Deoxycholic acid modified polymer (Dex-3DCA) can regulate the transformation of C_ (12) C_3C_ (12) Br_2/SDS mixed vesicles from spherical vesicles to rod like aggregates. For C_ (12) C_ (10) C_ (12) system, it can regulate The shape and size of (12) C_ (10) C_ (12) Br_2/SDS aggregates, while free Na DCA can dissolve the vesicle and change the number of layers and multicore vesicles. These results have important guiding significance for the further expansion of the theoretical and Application Research of such complex systems. The functional regulation of polymers on vesicle aggregates is of great theoretical and practical significance in drug entrapment and release.

【学位授予单位】：河南师范大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O647.2

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