壳聚糖的化学改性及其衍生物的抗氧化活性研究进展

摘 要壳聚糖是一种天然无毒的生物聚合物,主要经甲壳素的脱乙酰作用制得,具有良好的生物相容性、独特的抗氧化活性及生物可降解性等。由于壳聚糖在中性和碱性溶液中溶解性较差,其应用受到了一定限制,通常对其进行多种改性,拓宽其应用范围,提高其利用价值。近年来具有抗氧化能力的壳聚糖及壳聚糖衍生物表现出了优越的医用价值。本文综述了几种壳聚糖常用的改性方法,并介绍了壳聚糖及其衍生物作为抗氧化剂应用的研究进展。     

两种新型可溶性羧甲基壳聚糖季铵盐的合成

壳聚糖与氯乙酸在碱性条件下反应得到羧甲基壳聚糖，然后与芳香醛类反应得到壳聚糖 Schiff碱，还原后与碘甲烷反应生成可溶性的羧甲基壳聚糖季铵盐衍生物，经红外光谱仪（ FT－IR），氢核磁共振仪（1 H NMR）进行结构表征证实为两种新型羧甲基壳聚糖季铵盐，室温条件下两种壳聚糖季铵盐均可溶于水，不溶于环己烷和丙酮。     

磺化羟乙基壳聚糖的研制

研究了磺化羟乙基壳聚糖的制备方法。以片状壳聚糖为原料，先制成羟乙基壳聚糖；再以氯磷酸一甲酸胺为磺化试剂，在适当条件下进行磺化，成功地获得了水溶性良好的磺化羟乙基壳聚糖。硫含量为9．88％。红外光谱分析表明，该衍生物具有类肝素结构，是一种非常有潜力的新型类肝素物质，可望进一步研制成新型类肝素药物。     

酰化改性壳聚糖的合成及其性质考察

目的探讨疏水性壳聚糖衍生物作为口服药用不溶性骨架材料的可行性。方法以N-邻苯二甲酰壳聚糖为中间体,合成C6位被3种不同长度脂肪链完全酰化的壳聚糖衍生物,采用IR、1H-NMR、元素分析等方法对其结构进行表征;采用固定圆锥法测定壳聚糖衍生物流动性、压缩成形性及其在不同溶剂中的溶解性;以茶碱为模型药物,考察壳聚糖衍生物用于控制药物释放的可行性并初步探讨其释药机制。结果成功合成了3种壳聚糖衍生物并对其结构进行了表征;3种衍生物在有机溶剂中的溶解度显著提高,且具有很好的流动性和压缩成形性;单独使用该类衍生物制备的茶碱不溶性骨架片可显著延长释放时间至30 h,其释药机制以扩散为主,符合Huguch i方程。结论酰化改性壳聚糖衍生物加工性能和缓释作用良好,可用于口服不溶性骨架制剂,是一种良好的新型辅料。     

壳聚糖及其衍生物纳米粒的制备以及在疫苗中的应用

壳聚糖是一种高分子线性阳离子多糖。由壳聚糖及其化学改性衍生物制备的纳米粒具有生物相容性好、细胞毒性低以及可降解等特点,人们对其作为佐剂或递送系统在疫苗中的应用已开展了广泛研究。此文对壳聚糖及其衍生物纳米粒的制备方法以及在疫苗中的应用进行综述。     

半乳糖化季铵壳聚糖衍生物的设计、合成和表征

目的 合成和表征半乳糖化季铵壳聚糖衍生物作为潜在的肝靶向基因载体。方法 以天然聚合物壳聚糖为原料，首先制备季铵化壳聚糖，然后在其2-NH2上和乳糖酸反应，或与乳糖反应，用KBH4还原，制备得到未见文献报道的半乳糖化季铵壳聚糖衍生物。分别用FTIR,^1HNMR，^13CNMR和元素分析对其进行了表征。结果与结论 半乳糖化季铵壳聚糖衍生物有望作为潜在的肝靶向基因载体。     

O-羧甲基壳聚糖的吸湿、保湿性研究

目的:考察自制O-羧甲基壳聚糖的吸湿,保温性能.方法:以甘油,山梨醇为对照,采用称量法测定样品的吸湿率和水分残存率,研究自制O-羧甲基壳聚糖(O-CMC)的吸湿性和保湿性能,并与N,O-羧甲基壳聚糖(N,O-CMC),水溶性壳聚糖(CTS),壳聚糖盐酸盐(CTS·HCl)等壳聚糖及其他羧甲基壳聚糖衍生物进行比较.结果:48h后O-CMC,N,O-CMC,CTS,CTS·HCl及甘油,山梨醇在相对湿度(RH) 43％条件下的吸湿率分别为9％,11.7％,8.7％,6.78％,3.2％和1.1％;在RH82％条件下的吸湿率分别为42.2％,40.6％,35.32％,31.4％,24.4％和1.2％;在相对湿度RH43％条件下的水分残存率分别为159％,126％,124％,107％,93％和13％;在干硅胶条件下的水分残存率分别为68％,84％,66％,60％,27％和11％.结论:O-CMC的吸湿性和保温性能均优于壳聚糖及其他羧甲基壳聚糖衍生物,具有良好的吸湿,保湿性.     

壳聚糖在靶向制剂中的应用进展

壳聚糖是一种天然高分子化合物，壳聚糖及其衍生物具有优良的生物相容性和生物可降解性，在制药业有广阔的应用前景。综述了近几年来壳聚糖及其衍生物在靶向制剂中的应用。     

壳聚糖2-位NH2的修饰及其对理化性能的影响

目的制备结构相似、键型不同的壳聚糖（CTS）-水杨酸（醛、酮）系列衍生物，考察不同修饰物对溶解度和对金属离子吸附作用的影响。方法一步法制备水杨酰基和水杨醛基壳聚糖衍生物，用化学检识、热分析等方法对其进行表征，用返滴定法测定对Pb^2＋和Zn^2＋等重金属离子的吸附作用。结果CTS-水杨酰基系列衍生物的溶解度高于CTS的溶解度，且接枝率越高，溶解度越大；CTS-水杨醛基系列衍生物的溶解度低于CTS，接枝率越高，溶解度越低。2个系列修饰物对金属离子的吸附作用都低于CTS，且接枝率越高，吸附作用越低。但酰基衍生物对金属离子的吸附能力高于西佛碱衍生物。接枝率在50％以上时，西佛碱衍生物对Pb^2＋和Zn^2＋的吸附能力几乎为零；酰基衍生物对Pb^2＋仍具有一定的络合作用。结论水杨酰基壳聚糖的溶解度高于水杨醛基壳聚糖，CTS的2-位NH保留1个氢原子有助于提高修饰物的溶解度；高接枝率的水杨酰基-壳聚糖有可能成为Pb^2＋的高效解毒剂。     

壳聚糖及其衍生物在生物医学领域的应用研究进展

目的 为壳聚糖的开发利用提供参考.方法 从壳聚糖及其衍生物的来源、修饰改性方法及生物医学应用3方面进行总结.结果 壳聚糖的来源包括海产废弃物、陆地甲壳动物、植物、真菌等;修饰改性方法主要有酰化、烷基化、羧化、四元化、接枝共聚等化学方法,以及物理方法和酶法等;壳聚糖及其衍生物可作为抑菌剂、药物载体和组织工程材料应用.结论...     

吗替麦考酚酯纳米混悬剂的制备及其在兔眼内药动学研究

目的：研究普通吗替麦考酚酯纳米混悬剂及经壳聚糖修饰的吗替麦考酚酯纳米混悬剂在免眼角膜粘附性、泪液和房水药物动力学特性。方法：以薄膜分散一高压乳匀法制备纳米混悬剂,并进一步选用壳聚糖修饰纳米药物粒子制得具有粘附作用、带正电荷的壳聚糖修饰型纳米混悬剂。HPLC法检测角膜粘附、泪液和房水中的吗替麦考酚酯和霉酚酸的含量。结果：混悬剂滴眼液呈米黄色乳液状．纳米混悬剂和壳聚糖修饰型纳米混悬剂药物粒子呈圆球状,粒径均一,纳米混悬剂平均粒径59213111,多分散系数（Pdl）为0．114,Zeta为-29．6mV,壳聚糖修饰型纳米混悬剂平均粒径442hill,Pdl为0．096,Zeta为＋45mV。与普通混悬剂滴眼液相比,纳米混悬剂的角膜粘附性、泪液和房水中药物浓度明显提高,而壳聚糖修饰型纳米混悬剂则可进一步提高角膜粘附性和泪液、房水中药物浓度。结论：纳米混悬剂可以促进和提高吗替麦考酚酯眼局部给药后角膜粘附和药物吸收,而壳聚糖修饰型纳米混悬剂可进一步促进和提高药物的角膜粘附和吸收。     

两种壳聚糖修饰材料细胞相容性及蛋白吸附行为的评价

目的对甘油明胶/壳聚糖(CGG)和玉米醇溶蛋白/壳聚糖(ZC)两种壳聚糖修饰生物材料的细胞相容性和蛋白吸附作用进行初步评价。方法应用M TT比色法,评价两种材料对L 929小鼠细胞的细胞毒性,测定他们对大鼠原代表皮细胞的细胞粘附率和细胞增殖率;同时应用考马斯亮兰G-250染色法测定材料对牛血清蛋白的吸附作用。结果本实验结果显示,两种壳聚糖修饰材料对L 929细胞生长抑制反应级别为1级或0级,属于无明显毒性作用。大鼠皮肤成纤维细胞在CGG上的粘附率和增殖率分别达到88.8%和96.0%;在ZC上的粘附率和增殖率分别达到80.7%和94.7%。两种材料不同时间对蛋白的吸附量存在有差异。结论两种修饰材料具有良好的细胞相容性,其中CGG在细胞体外增殖作用和蛋白吸附作用方面要优于单纯壳聚糖和ZC。     

A novel surface modified nitrendipine nanocrystals with enhancement of bioavailability and stability

In this study, chitosan, a cationic polymer with positive charge, was introduced to modify the nanocrystals of nitrendipine with negative charge. The nanocrystals were prepared via precipitation-high pressure homogenization method. Then the nanocrystals were dispersed into chitosan solution, and the free chitosan was removed by centrifugation to obtain the chitosan modified nanocrystals, which remained the same particle size. However, the zeta-potential changed to positive after modification. The physical stability of the chitosan modified nanocrystals was remarkably improved under ambient conditions. During the in vitro dissolution test, the modified nanocrystals showed a certain degree of slow-release property. In the in vivo study, the C(max) of nitrendipine remained the same, however, the T(max) delayed from 0.75 h to 1.5 h with the chitosan modified nanocrystals. The surface modification by chitosan improved the bioavailability compared with the initial nanocrystals, which had demonstrated significant improvement of bioavailability compared to the traditional coarse powder form. Based on the experimental results, modification of the nanocrystals with certain polymer was supposed to be a good method to control the in vitro and in vivo behaviors of the nanocrystals, which could further increase the bioavailability of the water insoluble drug.     

羧甲基壳聚糖的制备与质量分析

用氯乙酸对壳聚糖进行了化学改性,其产物羧甲基壳聚糖有良好的水溶性。还对此产物进行了质量分析。     

Chitosan/gelatin microspheres prepared by modified emulsification and ionotropic gelation

Chitosan microspheres were prepared by an emulsion-phase separation technique without the use of chemical cross-linking agents; alternatively, ionotropic gelation was employed in a w/o emulsion. The possibility of three kinds of anions (tripolyphosphate, citrate and sulphate) to interact with chitosan was investigated by turbidimetric titration. The results indicate that there are electrostatic interactions between the above anions and chitosan in a certain region of solution pH (1.0-7.5 for sulphate/chitosan, 4.5-7.5 for citrate/chitosan and 1.9-7.5 for tripolyphosphate/chitosan), that is related to the natural characteristics of the anions. Out of the pH region where anions interact with chitosan, no microspheres were formed. However, even in the pH region where anions can interact with chitosan, only irregular microparticles were obtained in the case of the conventional emulsification and ionotropic gelation method, while spherical microspheres with diameters in the range of tens of microns were obtained when a modified process was employed. The key point of the modified process is the introduction of gelatin and allowing the ionic cross-linking process of chitosan/gelatin w/o emulsions to take place under coagulation conditions at a low temperature. The surface of sodium sulphate cross-linked chitosan/gelatin and sodium citrate cross-linked chitosan/gelatin microspheres was very smooth, but large gaps were observed on the surface of tripolyphosphate/chitosan microspheres. The increase of stirring speed led to a decrease in diameter and a narrowing in size distribution.     

基因载体PEG化壳聚糖的制备及其表征

目的：用亲水性的聚乙二醇对壳聚糖进行改性，制备适用于基因转染的非病毒类裁体。方法：合成步骤共分三步。首先通过有机合成，将甲氧基聚乙二醇(mPEG)的羟基末端依次活化成为羧基和琥珀酰亚胺端基，形成mPEG-COOH活化物和mPEG-COONSu活化物；然后将亲水性的mPEG-COONSu活化物接枝到壳聚糖的氨基侧链上，得到改性了的壳聚糖-聚乙二醇接枝产物，应用波谱技术FTIR，^1H-NMR，^13C-NMR对中间产物和最终产物进行了表征。结果：在FTIR谱图上基本找到mPEG-COOH，mPEG-COONSu的特征峰；^1H-NMR再一次确认mPEG-COONSu的合成；^13C-NMR确认了壳聚糖-聚乙二醇接枝产物的存在。结论：mPEG-COONSu活化物通过接枝反应对壳聚糖进行改性，得到了PBG化壳聚糖。     

改性壳聚糖膜在兔眼中的降解及组织病理学观察

目的了解兔眼中壳聚糖膜的降解与生物相容性 ,观察眼组织的病理学变化。方法对兔眼实施小梁切除术 ,将不同相对分子质量改性壳聚糖膜 ,植入板层巩膜瓣下 ,分别于术后 1、4、1 2周处死 ,摘除眼球 ,病理切片 ,观察组织反应。结果在植入早期 1、4周时 ,局部组织出现明显的炎症反应 ,随时间的推移 ,改性壳聚糖膜的降解速度加快 ,1 2周时 ,已降解为碎屑状 ,炎症反应基本消失。结论改性壳聚糖膜植入兔眼内可降解吸收 ,对兔眼组织不产生病理性损害     

Preparation,Optimization and Characterization of Bovine Lactoferrin‐loaded Liposomes and Solid Lipid Particles Modified by Hydrophilic Polymers Using Factorial Design

Bioadhesive liposomes and solid lipid particles (SLPs) modified by pectin and chitosan for oral administration of bovine lactoferrin (bLf) were prepared using a 2⁴ full‐factorial design to identify the key formulation variables influencing particle size and drug entrapment efficiency (EE). Netlike structures of the polymer–particle mixture consisting of a polymeric network in which multiple particles were imbedded were observed by scanning electron microscopy (SEM). Chemical stability of bLf after encapsulation into pectin‐ and chitosan‐modified liposomes and SLPs was confirmed by Fourier transform infrared spectra (FTIR). Bovine lactoferrin was located within phospholipid bilayer, whereas in SLPs bLf was within the matrix. The crystalline nature of bLf after encapsulation was investigated by differential scanning calorimetry (DSC) of drug‐loaded particles, indicating amorphous dispersion of bLf in the polymer–lipid matrix of pectin‐ and chitosan‐modified liposomes and SLPs. In vivo pharmacokinetic investigation of bLf in pectin‐ and chitosan‐modified liposomes and SLPs showed prolonged mean residence time (MRT) of bLf in rat blood and increased the relative bioavailability (F_bio%) by 1.95‐ to 2.69‐fold compared with free bLf. The developed carrier systems are considered to be promising vehicles for oral delivery.     

Modified chitosans for oral drug delivery

The cationic polysaccharide chitosan has been extensively studied for oral drug delivery. In recent years, chemically modified chitosans developed in order to improve the properties of chitosan for oral drug delivery have gained increasing attention. Representatives of these novel polymers are trimethyl-chitosans, thiolated chitosans, carboxymethyl chitosan and derivatives, hydrophobic chitosans, chitosan succinate and phthalate, PEGylated chitosans and chitosan-enzyme inhibitor conjugates. Besides their use for oral delivery of therapeutic peptides and proteins, they have recently been evaluated regarding their potential for the delivery of other substance classes, including genes and efflux pump substrates. Within the current review, various modified chitosan derivatives, their properties and synthesis are discussed.     

羧甲基壳聚糖银的合成及抑菌实验的研究

目的研究羧甲基壳聚糖银的合成方法及其对金黄色葡萄球菌、铜绿假单胞菌、大肠埃希菌、肺炎克雷伯菌和变形杆菌的抑菌作用。方法对壳聚糖经化学修饰后的衍生物进行红外吸收光谱分析。用稀释法和凹环法对烧伤常见的病原菌进行抑菌实验。结果修饰后的衍生物经红外图谱分析表明 ,壳聚糖已被氯乙酸所修饰。羧甲基壳聚糖银对浓度均为 10 4 CFU/ml的金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌的抑菌率分别为 88%、80 .2 %和 75 .3%。羧甲基壳聚糖银和AgNO3 对金黄色葡萄球菌、铜绿假单胞菌的最低抑菌浓度相同 ,对大肠埃希菌的最低抑菌浓度则前者低于后者。结论羧甲基壳聚糖银对烧伤感染常见致病菌有抑制作用 ,它可作为一种新型的预防、治疗烧伤感染的药物。