壳聚糖衍生物的制备及其在药物载体中的应用研究
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摘要
壳聚糖衍生于甲壳素，是自然界中产量仅次于纤维素的天然高分子多糖。由于它具有生物相容性、生物可降解性、抗菌性、无细胞毒性以及非凡的蛋白亲和性等优异性能，在生物医药尤其是药物载体方面具有广阔的应用前景。然而，除稀盐酸、稀醋酸等水溶液外，壳聚糖不溶于水和有机溶剂。因此，其应用非常有限。为克服壳聚糖溶解性的不足，本论文采用化学方法，对壳聚糖进行结构改造并对其在药物载体中的应用做进一步研究。
一、羧甲基壳聚糖载药5-氟尿嘧啶靶向肿瘤细胞
本论文采用聚乙二醇分子链将叶酸靶向分子与羧甲基壳聚糖连接，构建一种靶向载药体系羧甲基壳聚糖-聚乙二醇-叶酸。采用核磁共振氢谱、红外光谱对叶酸-聚乙二醇-羧甲基壳聚糖连接物进行表征。采用结晶紫染色法分别对羧甲基壳聚糖、载药5-氟尿嘧啶的羧甲基壳聚糖对肿瘤细胞的毒性进行验证。采用MTT法，分别用羧甲基壳聚糖、叶酸-聚乙二醇-羧甲基壳聚糖载药5-氟尿嘧啶，对细胞表面表达叶酸受体的HeLa细胞系进行靶向给药研究。MTT实验结果显示，载药5-氟尿嘧啶的羧甲基壳聚糖-聚乙二醇-叶酸体系对HeLa细胞系的毒性远大于载药5-氟尿嘧啶的羧甲基壳聚糖对HeLa细胞系的毒性，说明叶酸受体介导的内吞作用可提高细胞对载药5-氟尿嘧啶的羧甲基壳聚糖-聚乙二醇-叶酸靶向载药体系的吸收效率。
二、N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵碳纳米管复合材料的制备与研究
本论文采用N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵以自组装方式对多壁碳纳米管进行非共价修饰，得到的壳聚糖季铵盐碳纳米管复合材料在水中具有良好的分散性和超高的稳定性。采用红外光谱、核磁共振氢谱、X-射线衍射以及差示量热扫描等对N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵进行表征。红外光谱、热重分析、zeta电位以及透射电子显微镜等表征结果一致表明，N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵与多壁碳纳米管发生自组装。透射电子显微镜观察分析结果显示，原多壁碳纳米管直径为9.5nm，而经N, N,N-三甲基-2-羟基丙基壳聚糖氯化铵非共价修饰的多壁碳纳米管复合材料直径为14.7nm。N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵多壁碳纳米管复合材料zeta电位为+7.37mV。热重分析结果显示，经非共价修饰的多壁碳纳米管复合材料大约含20wt%N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵。N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵碳纳米管复合材料在水中具有超高的稳定性，在12,000rpm的转速下离心20分钟未见聚集沉淀。
三、壳聚糖磁性药物载体的制备与研究
本论文采用原位法制备壳聚糖衍生物磁性药物载体，这种方法制备的磁性药物载体大小均一、分散性良好而且具有超高的稳定性。采用红外光谱、X-射线衍射光谱、透射电子显微镜、zeta电位、动态光散射、热重分析以及振动样品磁强计对样品进行表征。透射电子显微镜观察结果表明，本研究方法制备的磁纳米粒子、羧甲基壳聚糖磁纳米粒子以及壳聚糖季铵盐磁纳米粒子的平均粒径分别为10nm、12nm和11nm。而动态光散射测定的水合粒径则分别为68nm、77nm和162nm, zeta电位与磁纳米粒子包覆层的带电情况密切相关，根据包覆层壳聚糖衍生物带电性的不同，zeta电位分别为+40.3mV、–56.3mV。每毫升羧甲基壳聚糖磁纳米粒子、壳聚糖季铵盐磁纳米粒子或单纯的磁纳米粒子的固含量分别为：6.28mg/mL、7.41mg/mL和9.07mg/mL，原子吸收光谱的分析结果表明，每毫升羧甲基壳聚糖磁纳米粒子、壳聚糖季铵盐磁纳米粒子或单纯的磁纳米粒子的铁含量分别为：4.78mg/mL、5.09mg/mL和4.56mg/mL。振动样品磁强计测试结果显示，磁纳米粒子、羧甲基壳聚糖磁纳米粒子和壳聚糖季铵盐磁纳米粒子的磁滞回线呈顺磁行为，它们的饱和磁化强度分别为59.1、66.2和55.8emu/g。透射电子显微镜观察结果显示，磁纳米粒子、羧甲基壳聚糖以及壳聚糖季铵盐磁纳米粒子的形貌为圆球性或类椭圆球形，它们的粒径分别为10nm、12nm和11nm。红外光谱表征结果证明，磁纳米粒子分别含有羧甲基壳聚糖和壳聚糖季铵盐成分；热重分析结果表明，磁纳米粒子水分含量约为2%、羧甲基壳聚糖磁纳米粒子的羧甲基壳聚糖含量约为6%、壳聚糖季铵盐磁纳米粒子的壳聚糖季铵盐含量约为16%。 X射线衍射图谱表明，这些磁纳米粒子具有尖晶石的晶体结构；振动样品磁强计表征结果显示，这些样品均为顺磁性物质。
四、壳聚糖-β-环糊精偶合物的制备与表征
本论文采用β-环糊精与对硝基苯磺酰氯反应形成β-环糊精苯磺酸酯，然后与壳聚糖反应制备壳聚糖-β-环糊精偶合物。采用红外光谱、核磁共振氢谱、X-射线衍射以及元素分析等手段对纯化处理的偶合物进行表征。在壳聚糖-β-环糊精偶合物红外光谱中，1020cm-1波长处的峰为β-环糊精的-吡喃基振动吸收峰，1050cm-1波长处的峰为壳聚糖β-吡喃基的振动吸收峰。壳聚糖-β-环糊精的核磁共振氢谱可完整再现壳聚糖以及β-环糊精各个质子核磁共振峰，说明β-环糊精已成功连接到壳聚糖结构单元。壳聚糖-β-环糊精偶合物的X-射线衍射谱图显示，位于衍射角2θ=10°的衍射峰消失，而位于衍射角2θ=20°的衍射峰则大大减弱，这意味着β-环糊精连接到壳聚糖结构单元的2位氨基上。氮元素分析结果显示，β-环糊精在偶合物中的取代度为13%。
Chitosan，the second abundant polysaccharide existing in nature, is a derivative from chitin.Chitosan has many distinctive properties such as biocompatibility, biodegradability,antimicrobial activity, nontoxicity and remarkable affinity to proteins. However, owing to itsinsoluble either in water or in organic solvents except aqueous acids, application of chitosan islimited. To overcome this drawback, chitosan was converted to water-or organicsolvents-soluble derivatives using chemical modification for further applications.
1. Folate polyethylene glycol conjugated carboxymethyl chitosan for tumor targeteddelivery of5fluorouracil
In this study, folate acid (FA) was conjugated to carboxymethyl chitosan (CMCS) through apolyethylene glycol (PEG) spacer to form CMCS-PEG-FA. The resulting conjugates wereconfirmed by1H nuclear magnetic resonance(1H NMR) and infrared spectroscopy (FT-IR)detection. The cytotoxic effects of CMCS-PEG-FA and CMCS-PEG-FA-5-fluorouracil (5-FU)were determined by crystal violet stain assay. Hela cell line, which has high surface folatereceptors, and A549cell line, which contains low amount of surface folate receptor, were used todetect the5-FU delivery ability by CMCS-PEG-FA with the use of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazoliu bromide analysis (MTT). The MTT resultsrevealed that the cytotoxicity of (CMCS-5-FU)-PEG-FA on Hella cells was greater thanCMCS-5-FU, suggesting that folate receptor-mediated endocytosis might improve the cellularuptake efficiency of5-FU-loaded CMCS-PEG-FA.
2. Preparation and characterization of N-[(2-hydroxy-3-trimethylammonium)propyl]chitosan chloride（HTACC）/multi-walled carbon nanotubes(MWCNTs) compositematerial
In this study, self-assembly between water-soluble GTMAC-grafted chitosan derivatives(HTACC) and multiwalled carbon nanotubes(MWCNTs) has been successfully developed andthe resultant products possessed excellent dispersity. HTACC was characterized by FT-IR,1H-NMR, X-ray diffraction(XRD) and DSC. Spontaneous self-assembly complex of HTACCand MWCNTs was confirmed by FT-IR, thermogravimetric analysis(TGA), zeta potential, andtransmission electron microscopy(TEM) studies. TEM analysis revealed that the diameter ofpristine MWCNTs was9.5nm whereas the diameter of HTACC coated MWCNTs was14.7nm. The measured zeta potential of HTACC coated MWCNTs was+7.37mv. TGA resultdemonstrated that the MWNT/HTACC consisted of about20wt%HTACC. As a novelderivative of the MWNTs, this HTACC coated MWCNTs showed a remarkable stabilitywithout any observable aggregation after centrifugation at12,000rpm for20minutes.
3. Preparation and characterization of magnetic targeted chitosan derivatives drug carrier
In situ preparation of magnetic chitosan derivatives/Fe3O4composite nanoparticles wasemployed, resulting a uniform single-crystal and well-dispersible product. The resultantmagnetic Fe3O4nanoparticles were characterized with FT-IR, X-RD, TEM, zeta-potentialmeasurement and vibrating sample magnetometry (VSM). The synthetic protocol described inthis paper yielded materials, composed magnetite cores with the mean crystallite size among10nm and12nm. The mean hydrodynamic diameters of these particles varied from68nm to162nm, and the zeta potentials of the materials varied from highly positive+40.3mV to negative–56.3mV, depending on the coating material used. The magnetic nanoparticle concentration interms of iron content varied from4.56mg/L to5.09mg/L and the magnetic nanoparticleconcentration in terms of dry weight was6.28mg/mL～9.07mg/mL. The hysteresis loops ofFe3O4, carboxymethyl chitosan magnetic nanoparticles(Fe3O4/CMCS) and2-hydroxypropyltrimethyl ammonium chloride chitosan magnetic nanoparticles (Fe3O4/QCTS)nanoparticles showed a ferromagnetic behavior with saturation magnetization of59.1,66.2and55.8emu/g, respectively. TEM results demonstrated a spherical or ellipsoidal morphologywith an average diameter of10-12nm. The adsorbed layer of QCTS and CMCS on themagnetite surface was confirmed by FT-IR. TGA results indicated that the Fe3O4/QCTSconsisted of about16wt%QCTS and the CMCS content was about6%in Fe3O4/CMCS. XRDillustrated that the resultant magnetic nanoparticles had a spinel structure and lastly VSM resultsshowed the modified magnetic Fe3O4nanoparticles were superparamagnetic. The adsorptionmechanism of QCTS and CMCS onto the surface of Fe3O4nanoparticles was believed to be theelectrostatic and coordination interactions, respectively. The mechanisms of both QCTS andCMCS stabilizing the suspension of Fe3O4nanoparticles were supposed to be electrostaticrepulsion.
4. The preparation and characterization of chitosan-grafted-β-cyclodextrin
The conjugates of β-cyclodextrin with chitosan were obtained by the reaction ofβ-cyclodextrin with p-nitrobenzenesulfonyl chloride, following by grafting to chitosan. Thepurified conjugate was characterized with FT-IR,1H NMR, XRD and nitrogen analysis. In theinfrared spectra of chitosan-β-cyclodextrin, the peak at1020cm-1was ascribed to-pyanyl vibration of β-cyclodextrin and the peak at1050cm-1was due to β-pyanyl vibration of chitosan.Protons of both chitosan and cyclodextrins appeared in1H NMR of chitosan-β-cyclodextrinconjugate, indicating β-cyclodextrins was grafted to chitosan successfully. The XRD resultindicated that the peak at2θ=10°disappeared and the peak at2θ=20°decreased greatly,suggesting that β-cyclodextrin was grafted to2-position amino-group in the unit of chitosan.Nitrogen analysis demonstrated that the substitution of β-cyclodextrin was13%.
一、羧甲基壳聚糖载药5-氟尿嘧啶靶向肿瘤细胞
本论文采用聚乙二醇分子链将叶酸靶向分子与羧甲基壳聚糖连接，构建一种靶向载药体系羧甲基壳聚糖-聚乙二醇-叶酸。采用核磁共振氢谱、红外光谱对叶酸-聚乙二醇-羧甲基壳聚糖连接物进行表征。采用结晶紫染色法分别对羧甲基壳聚糖、载药5-氟尿嘧啶的羧甲基壳聚糖对肿瘤细胞的毒性进行验证。采用MTT法，分别用羧甲基壳聚糖、叶酸-聚乙二醇-羧甲基壳聚糖载药5-氟尿嘧啶，对细胞表面表达叶酸受体的HeLa细胞系进行靶向给药研究。MTT实验结果显示，载药5-氟尿嘧啶的羧甲基壳聚糖-聚乙二醇-叶酸体系对HeLa细胞系的毒性远大于载药5-氟尿嘧啶的羧甲基壳聚糖对HeLa细胞系的毒性，说明叶酸受体介导的内吞作用可提高细胞对载药5-氟尿嘧啶的羧甲基壳聚糖-聚乙二醇-叶酸靶向载药体系的吸收效率。
二、N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵碳纳米管复合材料的制备与研究
本论文采用N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵以自组装方式对多壁碳纳米管进行非共价修饰，得到的壳聚糖季铵盐碳纳米管复合材料在水中具有良好的分散性和超高的稳定性。采用红外光谱、核磁共振氢谱、X-射线衍射以及差示量热扫描等对N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵进行表征。红外光谱、热重分析、zeta电位以及透射电子显微镜等表征结果一致表明，N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵与多壁碳纳米管发生自组装。透射电子显微镜观察分析结果显示，原多壁碳纳米管直径为9.5nm，而经N, N,N-三甲基-2-羟基丙基壳聚糖氯化铵非共价修饰的多壁碳纳米管复合材料直径为14.7nm。N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵多壁碳纳米管复合材料zeta电位为+7.37mV。热重分析结果显示，经非共价修饰的多壁碳纳米管复合材料大约含20wt%N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵。N, N, N-三甲基-2-羟基丙基壳聚糖氯化铵碳纳米管复合材料在水中具有超高的稳定性，在12,000rpm的转速下离心20分钟未见聚集沉淀。
三、壳聚糖磁性药物载体的制备与研究
本论文采用原位法制备壳聚糖衍生物磁性药物载体，这种方法制备的磁性药物载体大小均一、分散性良好而且具有超高的稳定性。采用红外光谱、X-射线衍射光谱、透射电子显微镜、zeta电位、动态光散射、热重分析以及振动样品磁强计对样品进行表征。透射电子显微镜观察结果表明，本研究方法制备的磁纳米粒子、羧甲基壳聚糖磁纳米粒子以及壳聚糖季铵盐磁纳米粒子的平均粒径分别为10nm、12nm和11nm。而动态光散射测定的水合粒径则分别为68nm、77nm和162nm, zeta电位与磁纳米粒子包覆层的带电情况密切相关，根据包覆层壳聚糖衍生物带电性的不同，zeta电位分别为+40.3mV、–56.3mV。每毫升羧甲基壳聚糖磁纳米粒子、壳聚糖季铵盐磁纳米粒子或单纯的磁纳米粒子的固含量分别为：6.28mg/mL、7.41mg/mL和9.07mg/mL，原子吸收光谱的分析结果表明，每毫升羧甲基壳聚糖磁纳米粒子、壳聚糖季铵盐磁纳米粒子或单纯的磁纳米粒子的铁含量分别为：4.78mg/mL、5.09mg/mL和4.56mg/mL。振动样品磁强计测试结果显示，磁纳米粒子、羧甲基壳聚糖磁纳米粒子和壳聚糖季铵盐磁纳米粒子的磁滞回线呈顺磁行为，它们的饱和磁化强度分别为59.1、66.2和55.8emu/g。透射电子显微镜观察结果显示，磁纳米粒子、羧甲基壳聚糖以及壳聚糖季铵盐磁纳米粒子的形貌为圆球性或类椭圆球形，它们的粒径分别为10nm、12nm和11nm。红外光谱表征结果证明，磁纳米粒子分别含有羧甲基壳聚糖和壳聚糖季铵盐成分；热重分析结果表明，磁纳米粒子水分含量约为2%、羧甲基壳聚糖磁纳米粒子的羧甲基壳聚糖含量约为6%、壳聚糖季铵盐磁纳米粒子的壳聚糖季铵盐含量约为16%。 X射线衍射图谱表明，这些磁纳米粒子具有尖晶石的晶体结构；振动样品磁强计表征结果显示，这些样品均为顺磁性物质。
四、壳聚糖-β-环糊精偶合物的制备与表征
本论文采用β-环糊精与对硝基苯磺酰氯反应形成β-环糊精苯磺酸酯，然后与壳聚糖反应制备壳聚糖-β-环糊精偶合物。采用红外光谱、核磁共振氢谱、X-射线衍射以及元素分析等手段对纯化处理的偶合物进行表征。在壳聚糖-β-环糊精偶合物红外光谱中，1020cm-1波长处的峰为β-环糊精的-吡喃基振动吸收峰，1050cm-1波长处的峰为壳聚糖β-吡喃基的振动吸收峰。壳聚糖-β-环糊精的核磁共振氢谱可完整再现壳聚糖以及β-环糊精各个质子核磁共振峰，说明β-环糊精已成功连接到壳聚糖结构单元。壳聚糖-β-环糊精偶合物的X-射线衍射谱图显示，位于衍射角2θ=10°的衍射峰消失，而位于衍射角2θ=20°的衍射峰则大大减弱，这意味着β-环糊精连接到壳聚糖结构单元的2位氨基上。氮元素分析结果显示，β-环糊精在偶合物中的取代度为13%。
Chitosan，the second abundant polysaccharide existing in nature, is a derivative from chitin.Chitosan has many distinctive properties such as biocompatibility, biodegradability,antimicrobial activity, nontoxicity and remarkable affinity to proteins. However, owing to itsinsoluble either in water or in organic solvents except aqueous acids, application of chitosan islimited. To overcome this drawback, chitosan was converted to water-or organicsolvents-soluble derivatives using chemical modification for further applications.
1. Folate polyethylene glycol conjugated carboxymethyl chitosan for tumor targeteddelivery of5fluorouracil
In this study, folate acid (FA) was conjugated to carboxymethyl chitosan (CMCS) through apolyethylene glycol (PEG) spacer to form CMCS-PEG-FA. The resulting conjugates wereconfirmed by1H nuclear magnetic resonance(1H NMR) and infrared spectroscopy (FT-IR)detection. The cytotoxic effects of CMCS-PEG-FA and CMCS-PEG-FA-5-fluorouracil (5-FU)were determined by crystal violet stain assay. Hela cell line, which has high surface folatereceptors, and A549cell line, which contains low amount of surface folate receptor, were used todetect the5-FU delivery ability by CMCS-PEG-FA with the use of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylterazoliu bromide analysis (MTT). The MTT resultsrevealed that the cytotoxicity of (CMCS-5-FU)-PEG-FA on Hella cells was greater thanCMCS-5-FU, suggesting that folate receptor-mediated endocytosis might improve the cellularuptake efficiency of5-FU-loaded CMCS-PEG-FA.
2. Preparation and characterization of N-[(2-hydroxy-3-trimethylammonium)propyl]chitosan chloride（HTACC）/multi-walled carbon nanotubes(MWCNTs) compositematerial
In this study, self-assembly between water-soluble GTMAC-grafted chitosan derivatives(HTACC) and multiwalled carbon nanotubes(MWCNTs) has been successfully developed andthe resultant products possessed excellent dispersity. HTACC was characterized by FT-IR,1H-NMR, X-ray diffraction(XRD) and DSC. Spontaneous self-assembly complex of HTACCand MWCNTs was confirmed by FT-IR, thermogravimetric analysis(TGA), zeta potential, andtransmission electron microscopy(TEM) studies. TEM analysis revealed that the diameter ofpristine MWCNTs was9.5nm whereas the diameter of HTACC coated MWCNTs was14.7nm. The measured zeta potential of HTACC coated MWCNTs was+7.37mv. TGA resultdemonstrated that the MWNT/HTACC consisted of about20wt%HTACC. As a novelderivative of the MWNTs, this HTACC coated MWCNTs showed a remarkable stabilitywithout any observable aggregation after centrifugation at12,000rpm for20minutes.
3. Preparation and characterization of magnetic targeted chitosan derivatives drug carrier
In situ preparation of magnetic chitosan derivatives/Fe3O4composite nanoparticles wasemployed, resulting a uniform single-crystal and well-dispersible product. The resultantmagnetic Fe3O4nanoparticles were characterized with FT-IR, X-RD, TEM, zeta-potentialmeasurement and vibrating sample magnetometry (VSM). The synthetic protocol described inthis paper yielded materials, composed magnetite cores with the mean crystallite size among10nm and12nm. The mean hydrodynamic diameters of these particles varied from68nm to162nm, and the zeta potentials of the materials varied from highly positive+40.3mV to negative–56.3mV, depending on the coating material used. The magnetic nanoparticle concentration interms of iron content varied from4.56mg/L to5.09mg/L and the magnetic nanoparticleconcentration in terms of dry weight was6.28mg/mL～9.07mg/mL. The hysteresis loops ofFe3O4, carboxymethyl chitosan magnetic nanoparticles(Fe3O4/CMCS) and2-hydroxypropyltrimethyl ammonium chloride chitosan magnetic nanoparticles (Fe3O4/QCTS)nanoparticles showed a ferromagnetic behavior with saturation magnetization of59.1,66.2and55.8emu/g, respectively. TEM results demonstrated a spherical or ellipsoidal morphologywith an average diameter of10-12nm. The adsorbed layer of QCTS and CMCS on themagnetite surface was confirmed by FT-IR. TGA results indicated that the Fe3O4/QCTSconsisted of about16wt%QCTS and the CMCS content was about6%in Fe3O4/CMCS. XRDillustrated that the resultant magnetic nanoparticles had a spinel structure and lastly VSM resultsshowed the modified magnetic Fe3O4nanoparticles were superparamagnetic. The adsorptionmechanism of QCTS and CMCS onto the surface of Fe3O4nanoparticles was believed to be theelectrostatic and coordination interactions, respectively. The mechanisms of both QCTS andCMCS stabilizing the suspension of Fe3O4nanoparticles were supposed to be electrostaticrepulsion.
4. The preparation and characterization of chitosan-grafted-β-cyclodextrin
The conjugates of β-cyclodextrin with chitosan were obtained by the reaction ofβ-cyclodextrin with p-nitrobenzenesulfonyl chloride, following by grafting to chitosan. Thepurified conjugate was characterized with FT-IR,1H NMR, XRD and nitrogen analysis. In theinfrared spectra of chitosan-β-cyclodextrin, the peak at1020cm-1was ascribed to-pyanyl vibration of β-cyclodextrin and the peak at1050cm-1was due to β-pyanyl vibration of chitosan.Protons of both chitosan and cyclodextrins appeared in1H NMR of chitosan-β-cyclodextrinconjugate, indicating β-cyclodextrins was grafted to chitosan successfully. The XRD resultindicated that the peak at2θ=10°disappeared and the peak at2θ=20°decreased greatly,suggesting that β-cyclodextrin was grafted to2-position amino-group in the unit of chitosan.Nitrogen analysis demonstrated that the substitution of β-cyclodextrin was13%.
引文
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