生物可降解壳聚糖—聚乳酸接枝共聚物的制备、表征与性能研究
摘要
壳聚糖是一种具有良好的生物相容性、生物降解性和生物活性的天然高分子,来源丰富。但是由于分子间的氢键相互作用,其难溶的性质,大大限制了壳聚糖的应用,接枝改性是改善壳聚糖性能的有效途径。聚乳酸具有一定的机械强度、生物相容性、生物降解性,作为生物医用材料受到了广泛重视。但是聚乳酸具有高结晶性、很强的疏水性,很大程度上限制了其在药物释放载体材料以及组织工程骨架材料上的应用。低分子量的壳聚糖具有良好的亲水性,将聚乳酸接枝到壳聚糖上制备壳聚糖接枝聚乳酸,既可以改善壳聚糖的机械性能,又可以改善聚乳酸的疏水性能,实现壳聚糖与聚乳酸两者性能互补,有望用于药物控释载体和组织工程材料,具有重要的理论研究价值和良好的应用前景。
本文提出两种新的方法制备壳聚糖接枝乳酸低聚物(CS-OLA),即分别采用N,N’-羰基二咪唑(N,N'-Carbonyldiimidazole, CDI)、N,N’-二环己基碳二亚胺(N,N'-Dicyclohexylcarbodiimide, DCC)充当偶联剂将左旋或右旋乳酸低聚物连接到壳聚糖对应氨基或羟基上。利用CS-ODLA和CS-OLLA中ODLA与OLLA链段间立体复合作用制备壳聚糖基物理水凝胶体系。深入研究壳聚糖接枝乳酸低聚物反应条件,并对CS-OLA立体复合水凝胶的凝胶结构和药物控制释放行为进行了考察。
首先以无毒的乳酸锌做催化剂,合成一系列分子量分布较窄的乳酸低聚物(OLA-OH),用CDI活化OLA-OH端羟基得到OLA-CI活性中间体,以4-二甲氨基吡啶(DMAP)为催化剂,将OLA-CI接枝到壳聚糖分子链上制备壳聚糖接枝乳酸低聚物(CS-OLA)。同时以无毒的乳酸锌做催化剂,合成一系列一端含羧基的乳酸低聚物(OLA-COOH), OLA-COOH端羧基被DCC活化后,在DMAP催化下,很容易与壳聚糖上C2-NH2、C6-OH反应,生成壳聚糖接枝乳酸低聚物(CS-OLA)。采用1H-NMR和FT-IR表征壳聚糖接枝乳酸低聚物合成反应。研究表明,壳聚糖C2-NH2反应活性比C6-OH高,OLA优先与C2-NH2反应。CS-OLA系列聚合物取代度与[CSunit]/[OLA]相接近,调节[CSunit]/[OLA]投料比值,可以得到不同取代度的CS-OLA聚合物。CS-OLA聚合物具有多样的溶解性,有助于制备纳米微粒或水凝胶。比较CDI和DCC充当偶联剂合成结果,OLA优先接枝到CS上C2-NH2位置,尤其在CS过量较大时,CS上C2-NH2反应活性明显高于CS上C6-OH。更为明显的是,DCC方法得到接枝共聚物取代度大于CDI方法,说明DCC方法的反应活性高于CDI方法。总体而言,合成CS-OLA接枝共聚物时,OLA聚合较低时,选用DCC方法比较好,OLA聚合度较高时,选用CD]方法比较适宜。
通过MTT实验评价CS-OLA聚合物的细胞相容性,CS-OLA聚合物都具有良好的细胞相容性,其中水溶性较好的10#-CS5K-OLA20C、6#-CS5K-OLA20D样品尤其突出。选用这两个样品制备壳聚糖接枝乳酸低聚物立体复合水凝胶。采用凝胶溶胀比、DSC、WAXD、SEM测试方法表征凝胶的结构,研究表明,CS-OLA中OLLA与ODLA链段间立体复合作用是CS-OLA立体复合水凝胶形成的原因,CS-OLA立体复合水凝胶以壳聚糖长链为骨架,OLLA与ODLA链段间立体复合结构为物理交联点的三维网状结构。CS-OLA取代度越大,凝胶结构越致密,溶胀比越低。
以胸腺五肽为模型药物,研究CS-OLA立体复合水凝胶药物控制释放性能。水凝胶药物控制性能与水凝胶结构、凝胶载药量有密切关系。致密的水凝胶结构,药物释放速率低,药物释放量少,释放量在75%以上,凝胶载药量对凝胶释放后期有影响,载药量高的凝胶后期释放速率比载药量低的凝胶高。壳聚糖接枝乳酸低聚物物理水凝胶体系可以在注射部位形成原位物理凝胶,具有优良的药物控制释放性能及生物相容性,可以预见在药物控释领域将得到广泛的应用。
Chitosan (CS) is a kind of natural macromolecules with excellent biocompatibility, biodegradability and bioactivity, and can be obtained from a wide range of natural sources. However, the intermoleculer hydrogen-bonding interactions contribute to its poor solubility in water and in many organic solvents, thus constraining its potential applications. Modification of CS by branding is an effective approach to improve its solubility. Poly(lactic acid) (PLA) presents outstanding mechanical strength, biocompatibility, and biodegradability, and has been attracting growing attention for various applications. Nevertheless, the high crystallinity and hydrophobicity of PLA greatly constrains its applications as drug-release carriers or tissue engineering scaffolds. Low molecular weight chitosan exhibits excellent hydrophilicity. Chitosan-Oligo(lactic acid) Graft Copolymers (CS-OLA), prepared by attaching OLA to CS backbone, will combine the mechanical strength of PLA with the hydrophilicity of CS. Therefore, CS-OLA presents great potential as controlled drug release carriers and tissue engineering scaffolds, which is of major importance for both fundamental research and pratical applications.
Two novel reaction routes were proposed to prepare CS-OLA, using N,N'-carbonyldiimidazole (CDI) or N,N'-Dicyclohexylcarbodiimide (DCC) as the coupling agent to attach OLA to the amino and/or hydroxy groups of CS. The reaction conditions of CS-OLA synthesis were investigated in detail. CS-based physical hydrogel systems were prepared through stereocomplexation between ODLA and OLLA segments of CS-OLA. The stereocomplexed structure and drug release behavior of hydrogels were evaluated.
A series of monodisperse hydroxyl-capped OLA (OLA-OH) were first synthesized using low toxic zinc lactate as initiator. OLA-OH was then activated by CDI to yield OLA-CI active intermediate. OLA-CI was finally coupled to the CS backbone to yield CS-OLA, usins DMAP as catalyst. In the meantime, carboxyl-capped OLA (OLA-COOH) was synthesized under similar conditions. Following the activation by DCC, OLA-COOH is readily attached to C2-NH2 and C6-OH of CS with DMAP as catalyst, thus yielding CS-OLA. Enhanced reactivity of C2-NH2 with respect to C6-OH was observed from 1H-NMR and FT-IR analyses. The degree of substitution of the CS-OLA was close to the molar ratio of [CSunit] to [OLA] in the feed, and could be adjusted by varying the feed ratio. The resulting CS-OLA graft copolymers present variable solubility, facilitating preparation of nano-particlcs or hydrogels. Comparison of the results obtained from CDI and DCC routes shows that OLA was attached to C2-NH2 on CS, especially when CS was in large excess, in agreement with the higher reactivity of C2-NH2 as compared to C6-OH of CS. Furthermore, the degree of substitution of CS-OLA obtained by DCC approach is higher than that by CDI approach. Altogether, DCC approach is preferable for the synthesis of CS-OLA with shorter OLA segments, while CDI approach is preferable with longer OLA segments.
The cytocompatibility of CS-OLA was determined via MTT assay. All the copolymers present excellent cytocompatibility, especially well water-soluble 10#-CS5K-OLA20C and 6#-CS5K-OLA20D. The latters were then selected to prepare CS-OLA stereocomplex hydrogels. The swelling ratio, DSC, WAXD, SEM measurements were employed to determine the hydrogel structure. Data showed that the formation of hydrogels results from stereocomplexation between ODLA and OLLA segments of CS-OLA. A three-dimensional network structure is formed with CS as framework and OLLA/ODLA stereo-complex as physical crosslinks. With increasing degree of substitution, the gel structure becomes denser and the swelling ratio decreases.
The drug release behavior of the hydrogels was investigated using thymopentin (TP-5) as model drug. A more compact hydrogel structure leads to lower drug release rate and total released ratio. The drug load also affects the release behavior:hydrogels with higher load exhibit an increased release rate at the later stage with respect to those with lower drug load. CS-OLA physical hydrogel is injectable and can be formed at the injection site in situ, which is very promising in the field of controlled drug release.
本文提出两种新的方法制备壳聚糖接枝乳酸低聚物(CS-OLA),即分别采用N,N’-羰基二咪唑(N,N'-Carbonyldiimidazole, CDI)、N,N’-二环己基碳二亚胺(N,N'-Dicyclohexylcarbodiimide, DCC)充当偶联剂将左旋或右旋乳酸低聚物连接到壳聚糖对应氨基或羟基上。利用CS-ODLA和CS-OLLA中ODLA与OLLA链段间立体复合作用制备壳聚糖基物理水凝胶体系。深入研究壳聚糖接枝乳酸低聚物反应条件,并对CS-OLA立体复合水凝胶的凝胶结构和药物控制释放行为进行了考察。
首先以无毒的乳酸锌做催化剂,合成一系列分子量分布较窄的乳酸低聚物(OLA-OH),用CDI活化OLA-OH端羟基得到OLA-CI活性中间体,以4-二甲氨基吡啶(DMAP)为催化剂,将OLA-CI接枝到壳聚糖分子链上制备壳聚糖接枝乳酸低聚物(CS-OLA)。同时以无毒的乳酸锌做催化剂,合成一系列一端含羧基的乳酸低聚物(OLA-COOH), OLA-COOH端羧基被DCC活化后,在DMAP催化下,很容易与壳聚糖上C2-NH2、C6-OH反应,生成壳聚糖接枝乳酸低聚物(CS-OLA)。采用1H-NMR和FT-IR表征壳聚糖接枝乳酸低聚物合成反应。研究表明,壳聚糖C2-NH2反应活性比C6-OH高,OLA优先与C2-NH2反应。CS-OLA系列聚合物取代度与[CSunit]/[OLA]相接近,调节[CSunit]/[OLA]投料比值,可以得到不同取代度的CS-OLA聚合物。CS-OLA聚合物具有多样的溶解性,有助于制备纳米微粒或水凝胶。比较CDI和DCC充当偶联剂合成结果,OLA优先接枝到CS上C2-NH2位置,尤其在CS过量较大时,CS上C2-NH2反应活性明显高于CS上C6-OH。更为明显的是,DCC方法得到接枝共聚物取代度大于CDI方法,说明DCC方法的反应活性高于CDI方法。总体而言,合成CS-OLA接枝共聚物时,OLA聚合较低时,选用DCC方法比较好,OLA聚合度较高时,选用CD]方法比较适宜。
通过MTT实验评价CS-OLA聚合物的细胞相容性,CS-OLA聚合物都具有良好的细胞相容性,其中水溶性较好的10#-CS5K-OLA20C、6#-CS5K-OLA20D样品尤其突出。选用这两个样品制备壳聚糖接枝乳酸低聚物立体复合水凝胶。采用凝胶溶胀比、DSC、WAXD、SEM测试方法表征凝胶的结构,研究表明,CS-OLA中OLLA与ODLA链段间立体复合作用是CS-OLA立体复合水凝胶形成的原因,CS-OLA立体复合水凝胶以壳聚糖长链为骨架,OLLA与ODLA链段间立体复合结构为物理交联点的三维网状结构。CS-OLA取代度越大,凝胶结构越致密,溶胀比越低。
以胸腺五肽为模型药物,研究CS-OLA立体复合水凝胶药物控制释放性能。水凝胶药物控制性能与水凝胶结构、凝胶载药量有密切关系。致密的水凝胶结构,药物释放速率低,药物释放量少,释放量在75%以上,凝胶载药量对凝胶释放后期有影响,载药量高的凝胶后期释放速率比载药量低的凝胶高。壳聚糖接枝乳酸低聚物物理水凝胶体系可以在注射部位形成原位物理凝胶,具有优良的药物控制释放性能及生物相容性,可以预见在药物控释领域将得到广泛的应用。
Chitosan (CS) is a kind of natural macromolecules with excellent biocompatibility, biodegradability and bioactivity, and can be obtained from a wide range of natural sources. However, the intermoleculer hydrogen-bonding interactions contribute to its poor solubility in water and in many organic solvents, thus constraining its potential applications. Modification of CS by branding is an effective approach to improve its solubility. Poly(lactic acid) (PLA) presents outstanding mechanical strength, biocompatibility, and biodegradability, and has been attracting growing attention for various applications. Nevertheless, the high crystallinity and hydrophobicity of PLA greatly constrains its applications as drug-release carriers or tissue engineering scaffolds. Low molecular weight chitosan exhibits excellent hydrophilicity. Chitosan-Oligo(lactic acid) Graft Copolymers (CS-OLA), prepared by attaching OLA to CS backbone, will combine the mechanical strength of PLA with the hydrophilicity of CS. Therefore, CS-OLA presents great potential as controlled drug release carriers and tissue engineering scaffolds, which is of major importance for both fundamental research and pratical applications.
Two novel reaction routes were proposed to prepare CS-OLA, using N,N'-carbonyldiimidazole (CDI) or N,N'-Dicyclohexylcarbodiimide (DCC) as the coupling agent to attach OLA to the amino and/or hydroxy groups of CS. The reaction conditions of CS-OLA synthesis were investigated in detail. CS-based physical hydrogel systems were prepared through stereocomplexation between ODLA and OLLA segments of CS-OLA. The stereocomplexed structure and drug release behavior of hydrogels were evaluated.
A series of monodisperse hydroxyl-capped OLA (OLA-OH) were first synthesized using low toxic zinc lactate as initiator. OLA-OH was then activated by CDI to yield OLA-CI active intermediate. OLA-CI was finally coupled to the CS backbone to yield CS-OLA, usins DMAP as catalyst. In the meantime, carboxyl-capped OLA (OLA-COOH) was synthesized under similar conditions. Following the activation by DCC, OLA-COOH is readily attached to C2-NH2 and C6-OH of CS with DMAP as catalyst, thus yielding CS-OLA. Enhanced reactivity of C2-NH2 with respect to C6-OH was observed from 1H-NMR and FT-IR analyses. The degree of substitution of the CS-OLA was close to the molar ratio of [CSunit] to [OLA] in the feed, and could be adjusted by varying the feed ratio. The resulting CS-OLA graft copolymers present variable solubility, facilitating preparation of nano-particlcs or hydrogels. Comparison of the results obtained from CDI and DCC routes shows that OLA was attached to C2-NH2 on CS, especially when CS was in large excess, in agreement with the higher reactivity of C2-NH2 as compared to C6-OH of CS. Furthermore, the degree of substitution of CS-OLA obtained by DCC approach is higher than that by CDI approach. Altogether, DCC approach is preferable for the synthesis of CS-OLA with shorter OLA segments, while CDI approach is preferable with longer OLA segments.
The cytocompatibility of CS-OLA was determined via MTT assay. All the copolymers present excellent cytocompatibility, especially well water-soluble 10#-CS5K-OLA20C and 6#-CS5K-OLA20D. The latters were then selected to prepare CS-OLA stereocomplex hydrogels. The swelling ratio, DSC, WAXD, SEM measurements were employed to determine the hydrogel structure. Data showed that the formation of hydrogels results from stereocomplexation between ODLA and OLLA segments of CS-OLA. A three-dimensional network structure is formed with CS as framework and OLLA/ODLA stereo-complex as physical crosslinks. With increasing degree of substitution, the gel structure becomes denser and the swelling ratio decreases.
The drug release behavior of the hydrogels was investigated using thymopentin (TP-5) as model drug. A more compact hydrogel structure leads to lower drug release rate and total released ratio. The drug load also affects the release behavior:hydrogels with higher load exhibit an increased release rate at the later stage with respect to those with lower drug load. CS-OLA physical hydrogel is injectable and can be formed at the injection site in situ, which is very promising in the field of controlled drug release.
引文
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