降解型可注射水凝胶的合成及其用于药物缓释和细胞培养的研究
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摘要
近年来,可注射水凝胶作为一种新型的生物医用高分子材料成为生物医学领域的研究热点之一。其中,可降解的多糖基可注射水凝胶由于其良好的生物相容性和生物降解性引起了人们的广泛关注。然而,该类水凝胶应用于临床尚存在一些亟待解决的问题,如源自动物体的多糖存在病原传递和批次稳定性的问题,无法大规模应用,需要寻找类似的多糖来取代；水凝胶的凝胶浓度较高,不利于实际操作；在多糖中引入非生物降解的合成高分子时,会带来一定的毒副作用；用于药物释放时,药物的理化性质和药物／水凝胶的相互作用未纳入考察的范围等。本论文工作针对上述问题展开了多糖基降解型可注射水凝胶的合成、表征及其作为药物缓释载体和细胞培养支架的应用等研究。
我们合成了一系列多糖基降解型可注射水凝胶,采用傅立叶变换红外光谱(FTIR)和核磁共振光谱(H NMR)对其结构进行了表征,采用扫描电子显微镜(SEM)观察了水凝胶的内部形貌,通过倒置法和紫外透光率测定了凝胶化时间,通过称重法考察了水凝胶在磷酸盐缓冲液(PBS)中的溶胀行为及降解行为,采用四甲基偶氮唑盐微量酶反应比色法(MTT法)初步评价了水凝胶的生物相容性,研究了可注射水凝胶作为药物释放载体和细胞培养支架的可行性。具体研究内容如下：
1.制备了氧化羧甲基纤维素/N-琥珀酰基壳聚糖(OCMC/NSC)可注射水凝胶,用FTIR表征了其结构,考察了OCMC的氧化度对可注射水凝胶的凝胶化时间、溶胀行为及降解行为的影响。采用MTT法考察了水凝胶的生物相容性。以牛血清蛋白(BSA)为模型药物考察了OCMC/NSC可注射水凝胶的释药行为,并通过荧光光谱法考察了释放后的BSA的构象变化。研究发现,OCMC的氧化度越大,水凝胶的凝胶化时间越短,溶胀比越低,降解速率越慢。OCMC/NSC可注射水凝胶无明显细胞毒性。水凝胶对BSA有一定的缓释作用,且释放后的BSA的构象未发生变化。该研究表明,基于席夫碱交联反应的可注射水凝胶在形成过程中不需要引入其他引发剂或交联剂,可避免该类物质的毒副作用。
2.采用硫酸软骨素(ChS)和壳聚糖(CS)制备了可生物降解的可注射水凝胶,重点考察了大分子上醛基和氨基的比例对可注射水凝胶的性能的影响,如凝胶化时间、交联密度、交联点间平均分子量、机械性能、溶胀行为及降解行为。体外细胞毒性实验表明,制备的水凝胶具有较好的生物相容性。将模型药物氨茶碱、吲哚美辛和溶菌酶通过简单的混合的方式负载到水凝胶内部。药物释放行为表明,药物的理化性质及药物/聚合物相互作用对药物的释放行为有重要影响。该研究将为新的药物递送体系的开发与应用提供思路。
3.将温敏性聚合物聚N-异丙基丙烯酰胺(PNIPAAm)接枝到羧甲基纤维素(CMC)的分子链上,制备了一种具有较低凝胶浓度、可降解的可注射水凝胶(CMC-g-PNIPAAm)。该凝胶的凝胶浓度为2 wt%,低于文献报道的其他PNIPAAm基水凝胶的凝胶浓度。该凝胶对HEK 293T细胞显示出良好的生物相容性。以溶菌酶为模型蛋白质药物,考察了CMC-g-PNIPAAm水凝胶对溶菌酶的体外释放行为,结果显示,接枝率较大的水凝胶对溶菌酶有一定的缓释作用。圆二色谱及荧光光谱表明,释放后溶菌酶的二级结构和三级结构没有发生变化。以溶壁微球菌(Micrococcus lysodeikticus)为底物,测定了释放后溶菌酶的活力,结果表明释放后溶菌酶的活力未受影响。以上研究结果表明该温敏型可注射水凝胶在蛋白质药物的缓控释方面有广阔的应用前景。
4.在硫酸软骨素(ChS)分子中引入了低分子量的PNIPAAm,合成了一种可生物降解的可注射水凝胶。PNIPAAm的合成采用可逆-加成断裂链转移(RAFT)聚合,以使其降解后可通过肾脏排出体外。测定了水凝胶的相转变行为及凝胶化时间,结果显示,水凝胶的相转变温度在室温与37℃之间,凝胶化时间在70 s到90 s范围内,便于实际操作。体外降解实验表明,水凝胶在37℃的透明质酸酶溶液(酶浓度为100 U/m1)中降解4周后,失重率大于40%。二维细胞培养和三维细胞培养结果显示,水凝胶具有良好的生物相容性,能保持细胞的存活及增殖能力。细胞在水凝胶内部分层分布。研究结果表明该可注射水凝胶有望用于细胞的三维培养载体。
As novel biomedical materials, injectable hydrogels show bright application perspective. Especially, degradable polysaccharide-based injectable hydrogels have been extensively studied due to their biodegradability and biocompatibility. However, several challenges still remain for clinical applications. For example, the polysaccharide derived from animal sources present the risk of batch-to-batch variations and the possibility of immune responses upon injection; critical gelation concentration at which gelation occurs is high; incorporating synthetic polymers into the backbone of polysaccharide may increase the cytotoxicity of the hydrogel when they are non-biodegradable and not readily cleared away from the body under physiological conditions; the physico-chemical properties of the drugs and drug-polymer interaction are not considered. In view of these problems, we synthesized a series of novel degradable polysaccharide-based injectable hydrogels and investigated their potential applications in drug delivery and cell culture.
A series of degradable polysaccharide-based injectable hydrogels were developed, and were characterized by Fourier transform infrared (FTIR) spectroscopy and 1H NMR. Scanning electron microscopy (SEM) was employed to investigate the porous structure of the hydrogels. Hydrogel gelation time was measured by the vial inversion method and UV/vis spectroscopy. The swelling and degradation behavior of the hydrogels in PBS were determined by weighing method. Cytotoxicity evaluation of the hydrogels were performed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The potential applications of the injectable hydrogels in drug delivery and cell culture were inveatigated. The detailed research contents are as follows:
1. Injectable hydrogels derived from oxidized carboxymethylcellulose (OCMC) and N-succinyl-chitosan (NSC) were prepared by Schiff base reaction. The gelation readily took place at physiological pH and temperature. Several parameters, such as matrix gelation time, equilibrium swelling ratio, matrix degradation rate and drug release profile, were investigated. The in vitro cytotoxicity studies showed that the OCMC/NSC hydrogels were non-cytotoxic. The controlled release profile of BSA was obtained. Importantly, activity of released BSA was retained. This newly described OCMC/NSC hydrogels formed without requiring additional initiators, crosslinkers or light sources, eliminating the toxicity associated with such agents.
2. Injectable and biodegradable hydrogels based on oxidized chondroitin sulfate (OChS) and N-succinyl-chitosan (NSC) were developed. We focused on the physical characteristics of the hydrogels (e.g. crosslinking density, molecular weight between crosslinks and mechanical strength) and the effects of physico-chemical properties of the drugs and drug-polymer interaction on drug release behaviors. The model drugs aminophylline, indomethacin and lysozyme were easily incorporated into the hydrogels by mixing with the gel precursors. Release studies showed that the physico-chemical properties of the drugs and drug-polymer interaction play an important role in drug release behaviors. The study provided necessary information for the design and development of novel drug delivery systems.
3. CMC-g-PNIPAAm copolymers were developed by decorating the backbone of carboxymethylcellulose (CMC) with linear chains of poly(N-isopropylacrylamide) (PNIPAAm), with the ultimate aim of synthesizing a biodegradable and injectable hydrogel that also possesses a low gelation concentration. Their aqueous solutions were found to undergo a reversible subphysiological phase transition at the concentration of 2 wt%. The value is much lower than that reported for many PNIPAAm-based copolymers. The phase transition behavior, gelation time, injectability, viscosity, swelling, degradation and cytocompatibility were explored. Lysozyme was used as the model drug. In vitro release of lysozyme from the injectable hydrogel was studied. Secondary and tertiary structure analysis and biological assays of the released protein showed that encapsulation and release did not affect the protein conformation and functionality. These results indicate that this biocompatible and injectable hydrogel system may be useful as a potential vehicle for therapeutic proteins for sustained release applications.
4. Biohybrid injectable hydrogels based on chondroitin sulfate (ChS) and poly(N-isopropylacrylamide) (PNIPAAm) were developed. PNIPAAm was synthesized at various molecular weights by RAFT polymerization. The molecular weight range suitable for renal clearance was an important factor in the experimental design. The phase transition temperature was between room temperature and 37℃and the gelation time was 70-90 s, indicating their possibility for further clinical application. Hydrogel degradation was determined in PBS with 100 U/ml of hyaluronidase at 37℃and the results revealed that the hydrogels lost above 40% of their weight after 4 weeks. In vitro two-dimensional (2-D) and three-dimensional (3-D) cell cultures were performed. Cells demonstrated excellent viability when cultured with the hydrogel. In addition, the arrangement of multiple cell layers in the hydrogel was achieved. These results indicate the injectable hydrogels may be expected to have wide potential applications as a vehicle for the delivery of therapeutic cells.
我们合成了一系列多糖基降解型可注射水凝胶,采用傅立叶变换红外光谱(FTIR)和核磁共振光谱(H NMR)对其结构进行了表征,采用扫描电子显微镜(SEM)观察了水凝胶的内部形貌,通过倒置法和紫外透光率测定了凝胶化时间,通过称重法考察了水凝胶在磷酸盐缓冲液(PBS)中的溶胀行为及降解行为,采用四甲基偶氮唑盐微量酶反应比色法(MTT法)初步评价了水凝胶的生物相容性,研究了可注射水凝胶作为药物释放载体和细胞培养支架的可行性。具体研究内容如下：
1.制备了氧化羧甲基纤维素/N-琥珀酰基壳聚糖(OCMC/NSC)可注射水凝胶,用FTIR表征了其结构,考察了OCMC的氧化度对可注射水凝胶的凝胶化时间、溶胀行为及降解行为的影响。采用MTT法考察了水凝胶的生物相容性。以牛血清蛋白(BSA)为模型药物考察了OCMC/NSC可注射水凝胶的释药行为,并通过荧光光谱法考察了释放后的BSA的构象变化。研究发现,OCMC的氧化度越大,水凝胶的凝胶化时间越短,溶胀比越低,降解速率越慢。OCMC/NSC可注射水凝胶无明显细胞毒性。水凝胶对BSA有一定的缓释作用,且释放后的BSA的构象未发生变化。该研究表明,基于席夫碱交联反应的可注射水凝胶在形成过程中不需要引入其他引发剂或交联剂,可避免该类物质的毒副作用。
2.采用硫酸软骨素(ChS)和壳聚糖(CS)制备了可生物降解的可注射水凝胶,重点考察了大分子上醛基和氨基的比例对可注射水凝胶的性能的影响,如凝胶化时间、交联密度、交联点间平均分子量、机械性能、溶胀行为及降解行为。体外细胞毒性实验表明,制备的水凝胶具有较好的生物相容性。将模型药物氨茶碱、吲哚美辛和溶菌酶通过简单的混合的方式负载到水凝胶内部。药物释放行为表明,药物的理化性质及药物/聚合物相互作用对药物的释放行为有重要影响。该研究将为新的药物递送体系的开发与应用提供思路。
3.将温敏性聚合物聚N-异丙基丙烯酰胺(PNIPAAm)接枝到羧甲基纤维素(CMC)的分子链上,制备了一种具有较低凝胶浓度、可降解的可注射水凝胶(CMC-g-PNIPAAm)。该凝胶的凝胶浓度为2 wt%,低于文献报道的其他PNIPAAm基水凝胶的凝胶浓度。该凝胶对HEK 293T细胞显示出良好的生物相容性。以溶菌酶为模型蛋白质药物,考察了CMC-g-PNIPAAm水凝胶对溶菌酶的体外释放行为,结果显示,接枝率较大的水凝胶对溶菌酶有一定的缓释作用。圆二色谱及荧光光谱表明,释放后溶菌酶的二级结构和三级结构没有发生变化。以溶壁微球菌(Micrococcus lysodeikticus)为底物,测定了释放后溶菌酶的活力,结果表明释放后溶菌酶的活力未受影响。以上研究结果表明该温敏型可注射水凝胶在蛋白质药物的缓控释方面有广阔的应用前景。
4.在硫酸软骨素(ChS)分子中引入了低分子量的PNIPAAm,合成了一种可生物降解的可注射水凝胶。PNIPAAm的合成采用可逆-加成断裂链转移(RAFT)聚合,以使其降解后可通过肾脏排出体外。测定了水凝胶的相转变行为及凝胶化时间,结果显示,水凝胶的相转变温度在室温与37℃之间,凝胶化时间在70 s到90 s范围内,便于实际操作。体外降解实验表明,水凝胶在37℃的透明质酸酶溶液(酶浓度为100 U/m1)中降解4周后,失重率大于40%。二维细胞培养和三维细胞培养结果显示,水凝胶具有良好的生物相容性,能保持细胞的存活及增殖能力。细胞在水凝胶内部分层分布。研究结果表明该可注射水凝胶有望用于细胞的三维培养载体。
As novel biomedical materials, injectable hydrogels show bright application perspective. Especially, degradable polysaccharide-based injectable hydrogels have been extensively studied due to their biodegradability and biocompatibility. However, several challenges still remain for clinical applications. For example, the polysaccharide derived from animal sources present the risk of batch-to-batch variations and the possibility of immune responses upon injection; critical gelation concentration at which gelation occurs is high; incorporating synthetic polymers into the backbone of polysaccharide may increase the cytotoxicity of the hydrogel when they are non-biodegradable and not readily cleared away from the body under physiological conditions; the physico-chemical properties of the drugs and drug-polymer interaction are not considered. In view of these problems, we synthesized a series of novel degradable polysaccharide-based injectable hydrogels and investigated their potential applications in drug delivery and cell culture.
A series of degradable polysaccharide-based injectable hydrogels were developed, and were characterized by Fourier transform infrared (FTIR) spectroscopy and 1H NMR. Scanning electron microscopy (SEM) was employed to investigate the porous structure of the hydrogels. Hydrogel gelation time was measured by the vial inversion method and UV/vis spectroscopy. The swelling and degradation behavior of the hydrogels in PBS were determined by weighing method. Cytotoxicity evaluation of the hydrogels were performed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay. The potential applications of the injectable hydrogels in drug delivery and cell culture were inveatigated. The detailed research contents are as follows:
1. Injectable hydrogels derived from oxidized carboxymethylcellulose (OCMC) and N-succinyl-chitosan (NSC) were prepared by Schiff base reaction. The gelation readily took place at physiological pH and temperature. Several parameters, such as matrix gelation time, equilibrium swelling ratio, matrix degradation rate and drug release profile, were investigated. The in vitro cytotoxicity studies showed that the OCMC/NSC hydrogels were non-cytotoxic. The controlled release profile of BSA was obtained. Importantly, activity of released BSA was retained. This newly described OCMC/NSC hydrogels formed without requiring additional initiators, crosslinkers or light sources, eliminating the toxicity associated with such agents.
2. Injectable and biodegradable hydrogels based on oxidized chondroitin sulfate (OChS) and N-succinyl-chitosan (NSC) were developed. We focused on the physical characteristics of the hydrogels (e.g. crosslinking density, molecular weight between crosslinks and mechanical strength) and the effects of physico-chemical properties of the drugs and drug-polymer interaction on drug release behaviors. The model drugs aminophylline, indomethacin and lysozyme were easily incorporated into the hydrogels by mixing with the gel precursors. Release studies showed that the physico-chemical properties of the drugs and drug-polymer interaction play an important role in drug release behaviors. The study provided necessary information for the design and development of novel drug delivery systems.
3. CMC-g-PNIPAAm copolymers were developed by decorating the backbone of carboxymethylcellulose (CMC) with linear chains of poly(N-isopropylacrylamide) (PNIPAAm), with the ultimate aim of synthesizing a biodegradable and injectable hydrogel that also possesses a low gelation concentration. Their aqueous solutions were found to undergo a reversible subphysiological phase transition at the concentration of 2 wt%. The value is much lower than that reported for many PNIPAAm-based copolymers. The phase transition behavior, gelation time, injectability, viscosity, swelling, degradation and cytocompatibility were explored. Lysozyme was used as the model drug. In vitro release of lysozyme from the injectable hydrogel was studied. Secondary and tertiary structure analysis and biological assays of the released protein showed that encapsulation and release did not affect the protein conformation and functionality. These results indicate that this biocompatible and injectable hydrogel system may be useful as a potential vehicle for therapeutic proteins for sustained release applications.
4. Biohybrid injectable hydrogels based on chondroitin sulfate (ChS) and poly(N-isopropylacrylamide) (PNIPAAm) were developed. PNIPAAm was synthesized at various molecular weights by RAFT polymerization. The molecular weight range suitable for renal clearance was an important factor in the experimental design. The phase transition temperature was between room temperature and 37℃and the gelation time was 70-90 s, indicating their possibility for further clinical application. Hydrogel degradation was determined in PBS with 100 U/ml of hyaluronidase at 37℃and the results revealed that the hydrogels lost above 40% of their weight after 4 weeks. In vitro two-dimensional (2-D) and three-dimensional (3-D) cell cultures were performed. Cells demonstrated excellent viability when cultured with the hydrogel. In addition, the arrangement of multiple cell layers in the hydrogel was achieved. These results indicate the injectable hydrogels may be expected to have wide potential applications as a vehicle for the delivery of therapeutic cells.
引文
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