多糖的化学改性及其水凝胶的敏感性研究
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摘要
天然多糖一般可分类为中性、酸性和碱性多糖,是大多数生物医用材料的主要原材料。酸性多糖透明质酸(HA)和碱性多糖壳聚糖(CS)以及中性多糖可德胶在药物控制释放领域,尤其是作为抗癌药物载体的研究越来越广泛。HA分子上面有癌细胞结合位点,具有癌症靶向性；CS为天然多糖中唯一的碱性多糖,可开发pH敏感性,作为药物载体在一定程度上也可以实现对癌细胞的pH靶向性；可德胶经过改性后,本身就可以作为一种抗癌药物,并可以作为药物载体。
本文从将多糖制备成水凝胶的新方法入手,通过分子设计,在多糖分子上引入敏感官能团,将多糖分子制备成具备环境敏感性的药物载体材料,研究多糖的敏感单元对不同环境变化的响应性来实现药物的可控释放,以期完成最终的水凝胶的智能载药。除了作为药物载体外,多糖通过一系列的分子设计,本身也可用作药物进行相应的治疗。
首先,以酸性HA为研究对象,用3-叠氮基-1-丙胺(3-azidopropan-1-amine,AA)和炔丙胺(2-propynylamine, PA)对HA进行改性,获得侧链带有炔基和叠氮基的HA,通过FTIR和1H NMR对改性后的HA结构进行表征,进而在硫酸亚铜和抗坏血钠催化的条件下,采用Click化学方法制备能够原位可注射用的HA水凝胶,通过表征确定水凝胶的溶胀率和交联程度成反比,并进一步用扫描电镜观察凝胶的形貌。
利用生物素(Biotin)和中性亲和素(Neutravidin)特异可逆的结合来制备HA微凝胶。首先通过己二酸二酰肼(ADH)改性HA获得带有氨基的HA分子,再利用N-羟基琥珀酰亚胺改性的Biotin,将Biotin接枝在HA分子上,利用Biotin和Avidin的结合来制备HA水凝胶。反应过程利用FTIR和1HNMR进行表征。在凝胶形成的过程中,可将DOX装载于HA微凝胶中,包封率和载药量可达到52.6%和3.8%。利用HA能够被肿瘤细胞表面高度表达HA受体CD44与HA介导自动性受体(RHAMM)所结合的特性,使得到的微凝胶抗肿瘤药物载体具备对肿瘤特异的靶向性。Biotin和Neutravidin可逆的结合,可以在过量Biotin存在的情况下触发HA微凝胶将装载于其中的抗癌药物定点释放出来。实验结果表明,在药物释放的过程中加入Biotin,可以加速药物的释放行为。
对于碱性多糖——壳聚糖(CS),由于其为阳离子型聚电解质,可以和阴离子或聚阴离子化合物反应形成网络结构的水凝胶。本文利用β-甘油磷酸钠(β-GP)制备具有温敏效应壳聚糖水凝胶,讨论溶液pH、β-GP的用量、壳聚糖的分子量以及温度对水凝胶性能的影响,发现在低温(4℃)状态,pH<5时,CS很难成凝胶。而当pH>5时,温度直接影响了CS成凝胶的能力,低温情况下依旧不能成凝胶。将抗癌药物盐酸阿霉素担载在温敏性CS凝胶中,并研究了药物的体外释放行为。
为了更好的实现壳聚糖凝胶温敏性,本文在CS分子接枝水溶性聚乙二醇单甲醚(mPEG),然后将温敏性的高分子聚N-异丙基丙烯酰胺(PNIPAM)接枝在共聚物CS-g-mPEG上,获得具有温度敏感壳聚糖水凝胶的原材料——CS-g-PNIPAM。首先,将CS-g-mPEG制备成原子转移自由基聚合(ATPR)用引发剂,采用ATRP法,引发N-异丙基丙烯酰胺(NIPAM)聚合,得到共聚物CS-g-PNIPAM,即温敏性壳聚糖。共聚物的结构和性能用FTIR、1H NMR和示差扫描量热(DSC)及热重分析(TG)来表征。结果表明,CS-g-mPEG热分解温度分布在166-500℃,摩尔接枝度为14.6%,分子量可达242500。CS的水溶性明显得到改善；共聚物CS-g-PNIPAM的聚合过程一级动力学显示出聚合过程具有良好的可控性,CS-g-PNIPAM的水溶性与CS-g-mPEG相似,最低临界共溶温度(LCST)值在32℃左右,在LCST以上,PNIPAM段可发生相转变进而获得可载药的微凝胶。
另外一种中性多糖——可德胶,也可以将其与PNIPAM接枝共聚来增加其水溶性,并引入温度敏感性。本文首先将可德胶进行羟基活化、溴化取代、叠氮反应来制备末端带有叠氮基团的可德胶(Curdlan-N3)。其次将α-2氯代异丙酸炔丙酯做为引发剂,N,N-二甲基甲酰胺(DMF)为溶剂,氯化亚铜/三-(N,N-二甲氨基乙基)胺(Me6TREN)为催化剂,采用ATRP法合成了末端带炔基的聚N-异丙基丙烯酰胺(PNIPAM-≡)。最后采用Click化学方法,以DMF和水为溶剂,五甲基二乙烯基三胺(PMDETA)和CuBr为催化剂,制备了接枝共聚物Curdlan-g-PNIPAM,其结构清楚且分子量分布较窄(PDI<1.35)。共聚物Curdlan-g-PNIPAM的结构和性能用FTIR、紫外光谱、1H NMR、GPC来表征。Curdlan-g-PNIPAM具备温敏性,其最低临界溶解温度(LSCT),大约在33℃左右。
Natural polysaccharides are classified as neutral, acidic and alkaline generally, which are the raw materials of most biomedical materials. Acidic polysaccharide hyaluronic acid (HA), alkaline polysaccharide chitosan (CS) and neutral polysaccharide curdlan are widely researched in the field of drug control and delivery, especially as carrier of anticancer drug. HA has ability of cancer targeting because HA molecular has the binding sites of cancer cells. While CS is the only alkaline polysaccharide in natural polysaccharides and pH sensitivity can be developed. When CS used as anticancer drug carrier, it will be perform pH targeting to a certain degree. Curdlan after modification can serve as a kind of anticancer drugs, and can be used as drug carrier.
This article prepared the polysaccharide hydrogels with new methods. Sensitive elements were introduced on polysaccharide molecules to prepare drug carrier with environmental sensitivity through the molecular design. Sensitive units on polysaccharides responded to different changes in the environment are researched to complete the final smart drug-loading hydrogels. Besides as drug carrier, polysaccharide through a series of molecule design can also be used as drugs on the corresponding treatment. First, acidic polysaccharide HA was used as research object.3-azidopropan-l-amine (AA) and2-propynylamine (PA) were selected to modify HA to get side chain of HA with azide or alkyne groups. FTTR and H NMR was used to characterize modified HA to confirm the reaction. Then in situ injection HA hydrogels were prepared using click chemistry with cuprous sulfate and sodium ascorbate as catalyst. Swelling ratio and crosslinking content of the hydrogels was inversely proportional. Forthemore, morphologies was observed by SEM.
In this study, HA micro-hydrogel was prepared by biotin-neutravidin system (BAS) specific reversible bonding. Firstly, carboxyl groups on HA were changed into amino groups with adipic acid dihydrazide (ADH) to graft with biotin by1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) named as HA-biotin. The results of synthesis procedure were characterized by1H-NMR and FTIR, ADH and biotin have been demonstrated to graft on HA molecule. When HA-biotin solution mixed with doxorubicin hydrochloride (DOX-HCl) was blended with neutravidin,the micro-hydrogels would be formed with DOX loading. The drug loading content and drug loading efficiency were3.8%and52.6%, respectively. HA has ability of cancer cell selectivity because two kinds of HA receptors:CD44and RHAMM are over-expressed in cancer cells. So HA is an attractive material used as anticancer drug carrier to perform cancer targeting. If excess biotin was added into the microgel, it would be disjointed and DOX will release quickly.
For alkaline polysaccharide, chitosan (CS) is cationic polyelectrolyte and can react with anion or polyanionic compounds to form the hydrogel with network structure. In the thesis, β-glycerophosphate (β-GP) was used to prepare chitosan hydrogels with thermosensitivity. The solution pH, dosage of (3-GP, chitosan molecular weight and temperature were discussed to find environment influence to CS hydrogels. The results indicated that CS was difficult to form hydrogel when the temperature was below4℃and solution pH<5. While when solution pH>5, temperature influenced the ability of CS hydrogels forming and CS can't form hydrogel under low temperature. Anticancer drug doxorubicin hydrochloride was loaded in thermosensitive CS hydrogel to investigate drug release behavior.
In order to perform better thermosensitivity and water-solubility of CS hydrogels, Methoxypolyethylene glycol (mPEG) was grafted on CS firstly, and then poly(N-isopropylacrylamide)(PNIPAM) was introduced on CS-g-mPEG molecular to obtain CS-g-PNIPAM that was an idea thermosensitive raw material to get thermosensitive CS hydrogels. CS-g-mPEG was used to prepare atom transfer radical polymerization (ATRP) initiator to initiate NIPAM polymerizating to get copolymer CS-g-mPEG. Structure and properties of copolymer CS-g-mPEG were characterized by FTIR,'H NMR, DSC and TG analysis. The results indicated that the thermal decomposition temperature of CS-g-mPEG was between166-500℃. The percentage of CS-g-mPEG grafting degree was14.6%, and the molecular weight can reach to242500. The water-solubility of CS-g-mPEG was similar to CS-g-PNIPAM and both of the copolymers were better than CS. The kinetics of polymerization showed polymerization with better controllability. The LCST of CS-g-PNIPAM was at about32℃. Above the LCST, PNIPAM segment on copolymer will occur phase transition to form microhydrogel to use as drug carrier.
Anthor neutral polysaccharide curdlan can also be grafted with PNIPAM to increase water-solubility and enhance thermosensitivity. In this thesis, curdlan were modified by hydroxyl activation, bromination and azide substitution to get curdlan-N3with an azido at the chain end. Then PNIPAM-≡were synthesized by ATRP using a-2chloro-isomethylacetic acid propargylester as initiator, dimethyl formamide as solvent and CuCl/tris (2-dimethyl/aminoethyl) amine as catalyst. At last,"click chemistry" was used to get copolymer Curdian-g-PNIPAM with dimethyl formamide and water as solvent and pentamethyl diethylenetriamine and CuBr as catalyst. The structure of copolymer was clear and molecular weight distribution was relatively low polydispersity (PDI<1.35). The structure and properties of copolymer Curdlan-g-PNIPAM were characterized by FT-IR, UV spectrum,1H NMR and GPC. Copolymer Curdlan-g-PNIPAM has the ability of thermosensitivity and the LCST were about33℃.
本文从将多糖制备成水凝胶的新方法入手,通过分子设计,在多糖分子上引入敏感官能团,将多糖分子制备成具备环境敏感性的药物载体材料,研究多糖的敏感单元对不同环境变化的响应性来实现药物的可控释放,以期完成最终的水凝胶的智能载药。除了作为药物载体外,多糖通过一系列的分子设计,本身也可用作药物进行相应的治疗。
首先,以酸性HA为研究对象,用3-叠氮基-1-丙胺(3-azidopropan-1-amine,AA)和炔丙胺(2-propynylamine, PA)对HA进行改性,获得侧链带有炔基和叠氮基的HA,通过FTIR和1H NMR对改性后的HA结构进行表征,进而在硫酸亚铜和抗坏血钠催化的条件下,采用Click化学方法制备能够原位可注射用的HA水凝胶,通过表征确定水凝胶的溶胀率和交联程度成反比,并进一步用扫描电镜观察凝胶的形貌。
利用生物素(Biotin)和中性亲和素(Neutravidin)特异可逆的结合来制备HA微凝胶。首先通过己二酸二酰肼(ADH)改性HA获得带有氨基的HA分子,再利用N-羟基琥珀酰亚胺改性的Biotin,将Biotin接枝在HA分子上,利用Biotin和Avidin的结合来制备HA水凝胶。反应过程利用FTIR和1HNMR进行表征。在凝胶形成的过程中,可将DOX装载于HA微凝胶中,包封率和载药量可达到52.6%和3.8%。利用HA能够被肿瘤细胞表面高度表达HA受体CD44与HA介导自动性受体(RHAMM)所结合的特性,使得到的微凝胶抗肿瘤药物载体具备对肿瘤特异的靶向性。Biotin和Neutravidin可逆的结合,可以在过量Biotin存在的情况下触发HA微凝胶将装载于其中的抗癌药物定点释放出来。实验结果表明,在药物释放的过程中加入Biotin,可以加速药物的释放行为。
对于碱性多糖——壳聚糖(CS),由于其为阳离子型聚电解质,可以和阴离子或聚阴离子化合物反应形成网络结构的水凝胶。本文利用β-甘油磷酸钠(β-GP)制备具有温敏效应壳聚糖水凝胶,讨论溶液pH、β-GP的用量、壳聚糖的分子量以及温度对水凝胶性能的影响,发现在低温(4℃)状态,pH<5时,CS很难成凝胶。而当pH>5时,温度直接影响了CS成凝胶的能力,低温情况下依旧不能成凝胶。将抗癌药物盐酸阿霉素担载在温敏性CS凝胶中,并研究了药物的体外释放行为。
为了更好的实现壳聚糖凝胶温敏性,本文在CS分子接枝水溶性聚乙二醇单甲醚(mPEG),然后将温敏性的高分子聚N-异丙基丙烯酰胺(PNIPAM)接枝在共聚物CS-g-mPEG上,获得具有温度敏感壳聚糖水凝胶的原材料——CS-g-PNIPAM。首先,将CS-g-mPEG制备成原子转移自由基聚合(ATPR)用引发剂,采用ATRP法,引发N-异丙基丙烯酰胺(NIPAM)聚合,得到共聚物CS-g-PNIPAM,即温敏性壳聚糖。共聚物的结构和性能用FTIR、1H NMR和示差扫描量热(DSC)及热重分析(TG)来表征。结果表明,CS-g-mPEG热分解温度分布在166-500℃,摩尔接枝度为14.6%,分子量可达242500。CS的水溶性明显得到改善；共聚物CS-g-PNIPAM的聚合过程一级动力学显示出聚合过程具有良好的可控性,CS-g-PNIPAM的水溶性与CS-g-mPEG相似,最低临界共溶温度(LCST)值在32℃左右,在LCST以上,PNIPAM段可发生相转变进而获得可载药的微凝胶。
另外一种中性多糖——可德胶,也可以将其与PNIPAM接枝共聚来增加其水溶性,并引入温度敏感性。本文首先将可德胶进行羟基活化、溴化取代、叠氮反应来制备末端带有叠氮基团的可德胶(Curdlan-N3)。其次将α-2氯代异丙酸炔丙酯做为引发剂,N,N-二甲基甲酰胺(DMF)为溶剂,氯化亚铜/三-(N,N-二甲氨基乙基)胺(Me6TREN)为催化剂,采用ATRP法合成了末端带炔基的聚N-异丙基丙烯酰胺(PNIPAM-≡)。最后采用Click化学方法,以DMF和水为溶剂,五甲基二乙烯基三胺(PMDETA)和CuBr为催化剂,制备了接枝共聚物Curdlan-g-PNIPAM,其结构清楚且分子量分布较窄(PDI<1.35)。共聚物Curdlan-g-PNIPAM的结构和性能用FTIR、紫外光谱、1H NMR、GPC来表征。Curdlan-g-PNIPAM具备温敏性,其最低临界溶解温度(LSCT),大约在33℃左右。
Natural polysaccharides are classified as neutral, acidic and alkaline generally, which are the raw materials of most biomedical materials. Acidic polysaccharide hyaluronic acid (HA), alkaline polysaccharide chitosan (CS) and neutral polysaccharide curdlan are widely researched in the field of drug control and delivery, especially as carrier of anticancer drug. HA has ability of cancer targeting because HA molecular has the binding sites of cancer cells. While CS is the only alkaline polysaccharide in natural polysaccharides and pH sensitivity can be developed. When CS used as anticancer drug carrier, it will be perform pH targeting to a certain degree. Curdlan after modification can serve as a kind of anticancer drugs, and can be used as drug carrier.
This article prepared the polysaccharide hydrogels with new methods. Sensitive elements were introduced on polysaccharide molecules to prepare drug carrier with environmental sensitivity through the molecular design. Sensitive units on polysaccharides responded to different changes in the environment are researched to complete the final smart drug-loading hydrogels. Besides as drug carrier, polysaccharide through a series of molecule design can also be used as drugs on the corresponding treatment. First, acidic polysaccharide HA was used as research object.3-azidopropan-l-amine (AA) and2-propynylamine (PA) were selected to modify HA to get side chain of HA with azide or alkyne groups. FTTR and H NMR was used to characterize modified HA to confirm the reaction. Then in situ injection HA hydrogels were prepared using click chemistry with cuprous sulfate and sodium ascorbate as catalyst. Swelling ratio and crosslinking content of the hydrogels was inversely proportional. Forthemore, morphologies was observed by SEM.
In this study, HA micro-hydrogel was prepared by biotin-neutravidin system (BAS) specific reversible bonding. Firstly, carboxyl groups on HA were changed into amino groups with adipic acid dihydrazide (ADH) to graft with biotin by1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCl) named as HA-biotin. The results of synthesis procedure were characterized by1H-NMR and FTIR, ADH and biotin have been demonstrated to graft on HA molecule. When HA-biotin solution mixed with doxorubicin hydrochloride (DOX-HCl) was blended with neutravidin,the micro-hydrogels would be formed with DOX loading. The drug loading content and drug loading efficiency were3.8%and52.6%, respectively. HA has ability of cancer cell selectivity because two kinds of HA receptors:CD44and RHAMM are over-expressed in cancer cells. So HA is an attractive material used as anticancer drug carrier to perform cancer targeting. If excess biotin was added into the microgel, it would be disjointed and DOX will release quickly.
For alkaline polysaccharide, chitosan (CS) is cationic polyelectrolyte and can react with anion or polyanionic compounds to form the hydrogel with network structure. In the thesis, β-glycerophosphate (β-GP) was used to prepare chitosan hydrogels with thermosensitivity. The solution pH, dosage of (3-GP, chitosan molecular weight and temperature were discussed to find environment influence to CS hydrogels. The results indicated that CS was difficult to form hydrogel when the temperature was below4℃and solution pH<5. While when solution pH>5, temperature influenced the ability of CS hydrogels forming and CS can't form hydrogel under low temperature. Anticancer drug doxorubicin hydrochloride was loaded in thermosensitive CS hydrogel to investigate drug release behavior.
In order to perform better thermosensitivity and water-solubility of CS hydrogels, Methoxypolyethylene glycol (mPEG) was grafted on CS firstly, and then poly(N-isopropylacrylamide)(PNIPAM) was introduced on CS-g-mPEG molecular to obtain CS-g-PNIPAM that was an idea thermosensitive raw material to get thermosensitive CS hydrogels. CS-g-mPEG was used to prepare atom transfer radical polymerization (ATRP) initiator to initiate NIPAM polymerizating to get copolymer CS-g-mPEG. Structure and properties of copolymer CS-g-mPEG were characterized by FTIR,'H NMR, DSC and TG analysis. The results indicated that the thermal decomposition temperature of CS-g-mPEG was between166-500℃. The percentage of CS-g-mPEG grafting degree was14.6%, and the molecular weight can reach to242500. The water-solubility of CS-g-mPEG was similar to CS-g-PNIPAM and both of the copolymers were better than CS. The kinetics of polymerization showed polymerization with better controllability. The LCST of CS-g-PNIPAM was at about32℃. Above the LCST, PNIPAM segment on copolymer will occur phase transition to form microhydrogel to use as drug carrier.
Anthor neutral polysaccharide curdlan can also be grafted with PNIPAM to increase water-solubility and enhance thermosensitivity. In this thesis, curdlan were modified by hydroxyl activation, bromination and azide substitution to get curdlan-N3with an azido at the chain end. Then PNIPAM-≡were synthesized by ATRP using a-2chloro-isomethylacetic acid propargylester as initiator, dimethyl formamide as solvent and CuCl/tris (2-dimethyl/aminoethyl) amine as catalyst. At last,"click chemistry" was used to get copolymer Curdian-g-PNIPAM with dimethyl formamide and water as solvent and pentamethyl diethylenetriamine and CuBr as catalyst. The structure of copolymer was clear and molecular weight distribution was relatively low polydispersity (PDI<1.35). The structure and properties of copolymer Curdlan-g-PNIPAM were characterized by FT-IR, UV spectrum,1H NMR and GPC. Copolymer Curdlan-g-PNIPAM has the ability of thermosensitivity and the LCST were about33℃.
引文
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