【作者】 麻金海；

【导师】 刘万顺；

【作者基本信息】 中国海洋大学 ， 海洋生物学， 2007， 博士

【摘要】 壳聚糖及其衍生物具有极好的生物特性,如生物降解性、无免疫原性、抗菌性和创口治疗活性等,已被广泛用作药物载体、抗菌剂、细胞培养载体及其它医用材料。另外通过与其它材料共混可以进一步改善壳聚糖的性能,尤其是力学性能;聚乳酸及其共聚物具有生物降解性和生物相容性,其嵌段共聚物可以自组装成纳米颗粒,已被用在组织工程、医疗装置和人工器官的培植、骨骼修复等各式各样的生物医用领域。将壳聚糖及其衍生物与乳酸共聚物进行有效复合可以制备出兼有二者优点的复合材料,而通过材料的简单混合很难实现这一目的。我们利用特定的单体制备出各种类型的乳酸共聚物和壳聚糖衍生物,通过它们之间的有序簇集与组装来制备这类纳米复合材料。主要结果如下:乳酸共聚物分子中的PLA链段的长短、侧链取代基团的亲水性或疏水性决定着分子的亲水-疏水平衡。PLA链段的疏水性决定了星形(star-shaped)乳酸共聚物(包括PLA-PTOL、PLA-GLU、PLA-LYS)的疏水性质;而PEG-2000链段的加入使乳酸-丁二酸-聚乙二醇-2000分子具有两亲性,成为典型的两亲嵌段共聚物;侧链含磺酸基团和季铵基团的乳酸共聚物(PLA-BDA-DTMPDOL、PLA-BDA-DTEAMPDOL)是典型的聚电解质;乳酸-丁二酸酐-2,2-二亚油酰基-1,3-丙二醇共聚物则是一种疏水性的梳形(combed)聚合物;壳聚糖改性后增加了分子的功能性。在2位氨基上离子化后,大大提高了分子的极性,使其溶于多种极性溶剂;在壳聚糖的2位氨基上接枝亚油酰基生成了疏水性的梳状聚合物,提高了其在非极性溶剂中的溶解性。通过选择不同的溶剂采用慢蒸发溶剂法制备出了以下三种有序簇集体:季戊四醇-乳酸四臂星形共聚物(PLA-PTOL)/壳聚糖(CS)、谷氨酸-乳酸三臂星形共聚物(PLA-GLU)/壳聚糖(CS)、赖氨酸-乳酸三臂星形共聚物(PLA-LYS)/壳聚糖(CS)。在不同溶剂中(三氯甲烷/甲醇-乙酸、三氯甲烷/二氯甲烷-三氯乙酸)生成的有序簇集体的形貌和尺寸差异较大;另外,随着星形分子的分子量的增加,三种超分子簇集体的尺寸都增大,但溶液的浓度对超分子簇集体的尺寸没有影响;IR结果表明,PLA-PTOL/CS超分子簇集体中的PLA-PTOL分子的C=O基与CS分子的OH基形成极强的氢键。三种星形分子与壳聚糖组装时放出的热量大约分别为8.6千焦/摩尔、5.6千焦/摩尔和5.6千焦/摩尔。两亲嵌段共聚物PLA-BDA-PEG-2000在极性溶剂如水、THF、乙醇和DMF中能够自组装成直径为几十个纳米到几个微米的聚合物实心球和空心球;球体尺寸随着分子中PLA聚合度的增大而增大;虽然溶液浓度对球径没有太大影响,但浓度过低时,球体形状变得不规则;自组装过程是一种自发的放热过程,每摩尔分子放出的热量大约为20.666千焦。梳形聚合物分子PLA-BDA-DLPDOL、(N-亚油酰基)壳聚糖、(N-亚油酰基,N-丁二酰基)壳聚糖在特定的溶剂中可以自身自发组装成有序簇集体,并且相互之间亦能自发组装成有序簇集体;亚油酰基的接枝率对簇集体的形貌有一定影响,同时溶剂类型对形貌也有较大影响,而溶液浓度对其却无影响;组装过程的热分析表明,梳形聚合物组装过程是放热的,并且(N-亚油酰基, N-丁二酰基)壳聚糖分子组装后存在蓝移现象。采用分子沉积法制备出了以下几种聚电解质自组膜:PLA-BDA-DTMPDOL/ N-(1-羟基-3-三甲胺)丙基壳聚糖,PLA-BDA-DTEAMPDOL/(N-丁二酰基)壳聚糖,PLA-BDA-DTEAMPDOL/ N-(2-羟基,3-磺酸)丙基壳聚糖。膜表面形貌与分子的离子度、溶解浓度有很大关系。离子度大,浓度适中可以得到表面较为致密的膜;切面形貌分析表明,自组膜的形成过程是一种不同电性聚合物分子有序的层-层组装过程。另外,组装成膜过程的热分析表明,成膜过程是放热的,自组膜是热力学稳定性体系;组装成膜后存在蓝移现象。不同类型的乳酸共聚物及壳聚糖衍生物尽管分子结构不同,但在一定的条件下均能自发进行分子的有序簇集和组装。产生组装的驱动力主要包括氢键、疏水-亲脂相互作用、静电相互作用等。有序簇集体的形貌随分子类型、外界条件等的不同而有差别。另外各种超分子簇集体都表现出良好的可降解性和较快的降解速度。更多还原

【Abstract】 Chitosan and its derivatives, showing excellent biological properties such as biodegradation in the human body, immunological, antibacterial, and wound-healing activity, are useful as carriers in drug delivery systems, as antibacterial agents, cell culture, and in other medical applications. Meanwhile, properties especially in strength could be improved through being mingled with other biomaterials. Poly(lactic acid) or its copolymers with other oligomers have been being used in such diverse biomedical fields as tissue engineering, implantation of medical devices and artifical organs, bone repair, et al, because of their biodegradable, biocompatible and self-assembling when the block copolymers are used for the prepration of nanoparticles. New muti-biomaterials nanoparticles with better biological properties can obtained throught the complexing of chitosan or its derivates with poly(lactic acid) or its copolymers, but we could not bring about the aim just throught simple complexing. So we have synthesized some peculiar structure derivates of chitosan and poly(lactic acid) in order to prepare muti-biomaterials nano-objects throught the ordered aggregating and self-assembling of these molecules. The main results are as follows:The length of the block PLA(hydrophilic) and the hydrophilic or hydrophobic property make the copolymers amphiphilic or not. Star-shaped polymers including PLA-PTOL(Poly[(lactic acd)-co-(pentaerythritol)]),PLA- GLU(Poly[(lactic acid)-co-(glutamic acid)]), and PLA-LYS(Poly[(lactic acid)- co-(lysine)]), show hydrophobic attribute to the block PLA; Poly[(lactic acid)-co-(butanedioic anhydridel))-co-(polyethylene glycol-2000l)](PLA-BDC- PEG-2000)as a typical block copolymer shows amphiphilic attribute to the block PLA and PEG-2000(hydrophilic); copolymers with taurinic or triethylaminic functional groups at side chains including Poly[(lactic acid)-co-(butanedioic anhydridel))-co-(2,2-ditaurinic-Methyl-1,3-propanediol)] (PLA-BDA-DTMPDOL) and Poly[(lactic acid)-co-(butanedioic anhydridel))- co- (2,2-ditriethylaminic-methyl-1,3-propanediol)](PLA-BDA-DTEAMPDOL) are typic- al polyelectrolyte; Poly[(lactic acid)-co-(butanedioic anhydridel))-co- (2,2- dilinoleonyl-1,3-propanediol)](PLA-BDA-DLPDOL) with linoleonyl fun- ctional groups at side chains is a hydrophobic combed polymer. Chitosan derivates modified by taurinic or triethylaminic functional groups at the C2 position show better polar than chitosan and can be dissolved in many polar solvents; chitosan derivates modified by linoleonyl functional groups at the C2 position called as combed polymer show better hydrophobic than chitosan and can be dissolved in many nonpolar solvents.The ordered molecular aggregates with different sorts of image and size, including PLA-PTOL/CS, PLA-GLU/CS, and PLA-LYS/CS have been prepared by slow evaporation of solvent in different sorts of solvents, such as CHCl3/CH3OH-AcOH, and CHCl3/CH2Cl2-CCl3CO2H. There are big differences in image and size because of solvents and molecular weight of these star-shaped polymers; but the density of polymers could not impact on the size of these ordered molecular aggregates; the aggregates grows larger with the increasing of molecular weight. It states that there are strong hydrogen bonds between C=O of PLA-PTOL and H-O of CS from FT-IR spectrums. The thermopositive values are 8.6kj/mol, 5.6kJ/mol, and 5.6kJ/mol in the self-assembling process of these three ordered molecular aggregates.Amphiphilic block copolymer (PLA-BDA-PEG-2000) can self-assemble and becomes solid and hollow balls in polar solvents such as H2O, THF, EtOH, and DMF. The size of balls grows larger with the increasing of the length of arms (PLA); density could not impact on the size of balls, but balls grow more irregular when density turns lower. The auto process of self-assembly is thermopositive and the value is 20.666kJ/mol. The ordered molecular aggregates can be obtained by self-assembly of combed polymers themselves and each other including PLA-BDA-DLPDOL, (N-linoleonyl)CS, and (N-butanoyl,N-linoleonyl ) CS. The graft ratio of linoleonyl to combed polymers and the types of solvents have effects on the images of ordered molecular aggregates, and density does not. The process is thermopositive and there are blue-shifts of covalent bond in FT-IR spectrums after self-assembling.Three polyelectrolyte membranes, including PLA-BDA-DTMPDOL/(N-(2- Hydroxyl-3-Trimethylamino)Propanyl)CS,PLA-BDA-DTEAMPDOL/(N-butanedioic)CS, and PLA-BDA-DTEAMPDOL/2-Hydroxyl-3-SulfoPropanyl)CS, have been prepared by molecular deposition. The surface images of these membranes have some changers with the changers of ion ratios and densities of polyelectrolyte molecules. Tight membranes can be obtained by increasing ion ratios and adjusting densities; the self-assembly process of these membranes is a lay-lay molecular self-assembly of polyelectrolytes with contrary electric charges. The process is thermopositive and there are blue-shifts of covalent bond in FT-IR spectrums after self-assembling.In a word, these different types of the derivatives of chitosan and poly(lactic acid), despite there are different molecular structures, all can do ordered gather and self-assemble automatically at a special condition. The forces of self-assembly include hydrogen bond, hydrophobic-lipophilic interaction, static electricity interaction, and et al. The images of the ordered aggregates differ from one another attributing to the type of polymer molecules and solvent, and et al. At same time, the ordered aggregates are biodegradable and have a fast biodegradation rate.更多还原