羰基官能团化聚己内酯共聚物合成、表征及其体外释药行为研究
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摘要
自20世纪90年代以来,聚己内酯(PCL)以其优越的生物可降解性,良好的生物相容性和药物通透性,受到人们的广泛关注。尤其是近几年来,随着高分子自组装技术的飞速发展,疏水性聚己内酯与亲水性聚合物形成两亲性共聚物在药物控释领域的研究越来越广泛。目前,制备具有生物相容、生物可降解性及智能响应性的药物载体是当前的研究热点和发展趋势。基于这一研究背景及发展趋势,本论文以4-羰基己内酯(OPD)为研究起点,将其与ε-己内酯(ε-CL)共聚,合成侧基悬挂羰基反应性官能团的聚己内酯共聚物(P(OPD-co-CL),并对其进行功能化改性得到含亲水性链段的嵌段和接枝共聚物。这些两亲性共聚物在选择性溶剂中能自发形成核-壳结构的聚合物胶束,利用其内核的特性,包载疏水性药物阿霉素(DOX)、油酸改性的Fe304纳米粒子以及5-氟尿嘧啶(5-Fu)。研究聚合物的自组装行为和体外释药行为。主要研究内容和结果如下：
1.通过经典的Baeyer-Villiger氧化反应将1,4-环己二酮转化为4-羰基己内酯,进而在甲氧基聚乙二醇(MPEG)为引发剂,异辛酸亚锡(Sn(Oct)2)为催化剂的条件下,与ε-CL开环聚合,合成了两亲性悬挂侧羰基反应性官能团的聚己内酯嵌段共聚物甲氧基聚乙二醇-b-聚(4-羰基己内酯-co-己内酯)(MPEG-b-P(OPD-co-CL))。探讨了本体聚合和溶液聚合两种聚合方法对聚合物结构的影响。利用核磁共振波谱(1HNMR)、差示扫描量热法(DSC)、热重分析法(TGA)和表面接触角研究了共聚物的结构和性能。实验结果表明采用溶液聚合可以成功地合成MPEG-b-(OPD-co-CL),而本体聚合由于其反应温度较高,所得到聚合物容易发生热降解。
2.采用透析的方法,制备了侧基悬挂羰基官能团的聚己内酯嵌段共聚物(MPEG-b-P(OPD-co-CL))胶束及其包载DOX的聚合物载药胶束。探讨了胶束的制备条件和OPD含量对聚合物的临界胶束浓度(CMC)和胶束粒径大小的影响。聚合物胶束粒径大小均一,单分散性好,呈规整的球形。羰基官能团的存在增加了聚合物胶束的稳定性和聚合物载药胶束在人体生理环境(pH7.4)中的缓释效果。
3.通过透析的方法,将油酸改性过的Fe304纳米粒子载入侧基悬挂羰基官能团的MPEG-b-(OPD-co-CL)胶束中,制备了大小均一、形态呈规整球状、具有良好磁响应性和稳定性的磁性聚合物胶束,并研究了包载DOX的磁性聚合载药胶束的药物释放行为。用磁滞回线、X-射线衍射(XRD)和TGA等手段对磁性聚合物胶束和磁性载药聚合物胶束进行了表征,发现聚合物胶束对磁性粒子和DOX药物的包埋导致它们的结晶性发生改变,确证了磁性纳米粒子和DOX载入胶束核中；磁性聚合物胶束的磁含量随羰基含量的增加而增加；DOX药物的载入对磁性聚合物胶束的磁含量没有太大影响；而磁性纳米粒子的载入对聚合物载药胶束的载药量和包封率影响也不大,且有利于增加聚合物载药胶束在人体生理环境(pH7.4)中的缓释效果。
4.以羟乙肼为桥,p-氯甲酸对硝基苯酯为偶联剂,合成了主链为聚己内酯(PCL),侧链为温敏性聚(N-异丙基丙烯酰胺)(PNIPAM)的接枝共聚物PCL-g-PNIPAM.用’HNMR、红外光谱(FTIR)和凝胶渗透光谱(GPC)确证了聚合物的结构。通过透射电镜(TEM),动态光散射(DLS),荧光光谱和紫外-可见光光谱及冷冻干燥后聚合物胶束在D20中的1H NMR波谱等研究了聚合物的自组装行为,结果表明该聚合物胶束具有温度和pH敏感性。另外,包载5-Fu药物的聚合物载药胶束在药物释放体系中表现出温度和pH敏感性的释放特征。
Poly(ε-caprolactone) (PCL) have drawn considerable attention due to its excellent biodegradability, biocompatibility and drug permeability since 1990s. Especially, over the last several years, with the rapid development of nano self-assembly techniques, amphiphilic copolymer composed of hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic polymers have been extensively studied in the field of drug delivery. Nowadays, the preparation of biocompatible, biodegradable and intelligent stimulus responsive drug delivery system is the current research focus and development trends. Base on this back ground and development trends, a functional poly(e-caprolactone) copolymer bearing reactive ketone groups (P(OPD-co-CL)) was developed using 2-oxepane-1,5-dione (OPD) as research starting point, and block copolymer and graft copolymer contain hydrophilic chain were also synthesized by further functional modification. All the amphiphilic polymers underwent self-assemble to form micelles and their loaded hydrophobic drug doxorubicin (DOX), oleic acid modified Fe3O4 nanoparticles and 5-fluorouracil (5-Fu) micelles were prepared by utilizing the charateristics of core. In addition, the drug release behavior of drug-loaded polymer micelles was also studied. Four sections of work were carried out as follows:
1. A amphiphilic functional block poly(ε-caprolactone) copolymer bearing ketone groups (MPEG-b-P(OPD-co-CL)) was synthesized.2-oxepane-1,5-dione (OPD) synthesized by Baeyer-Villiger oxidation of 1,4-cyclohexaedione was copolymerized withε-caprolatone (ε-CL) in which methoxy poly(ethylene glycol) (MPEG) and stannous octoate were used as initiator and catalyst, respectively. Both bulk and solution polymerization were adopted to investigate the effect of temperature on the structure of the copolymers. All the polymers were characterized by 1H-NMR, DSC, TGA and contact angle measurement. It demonstrated that the amphiphilic block copolymer with functional groups (MPEG-b-P(OPD-co-CL)) were successfully synthesized by solution polymerization. In constrast, the copolymers obtained by bulk polymerization were inclined to degrade due to the high reaction temperature.
2. Blank and DOX-loaded micelles of (MPEG-b-P(OPD-co-CL)) were prepared by a dialysis method. The effects of micelle preparation conditions and content of OPD on the critical micelle concentration (CMC) and size of polymer micelles were investigated. The polymer micelles showed uniform manodispersed spherical. The presence of ketone groups on PCL bolck is favorable to increase the thermodynamic stability of polymer micelles and sustained-release effect of drug-loaded polymer micelles in physiological environment (pH7.4).
3. With uniform size, regularly spherical shape, good magnetic responsiveness and stability of loaded oleic acid modified nano-Fe3O4 MPEG-b-(OPD-co-CL) micelles and loaded nano-Fe3O4 and DOX MPEG-b-(OPD-co-CL) micelles were carried out by a dialysis method. The drug release behavior of magnetic DOX-loaded polymer micelles was investigated. The magnetic polymer micelles and magnetic DOX-loaded polymer micelles were characterized by hysteresis loop, XRD and TGA. It was found that the polymer micelles containning oleic acid modified nano-Fe3O4 and DOX package leaded to a change in their crystalline, this result confirmed that the nano-Fe3O4 and DOX were loaded in the core of micelles; The content of nano-Fe3O4 increased with that of ketone groups increased in the hydrophobic chain, but the polymer micelles containning DOX package had little effect on the content of nano-Fe3O4. In addition, the polymer micelles containning oleic acid modified nano-Fe3O4 package also had no impact on the DLC and DEE, but are benificial to increase sustained-release effect of DOX-loaded polymer micelles in physiological environment (pH7.4).
4. The amphiphilic graft copolymers containing PCL as the hydrophobic main chain and poly(N-isopropylacrylamide) (PNIPAM) as the temperature-sensitive side chain on the side were synthesized. We use hydroxyethyl hydrazine and p-nitrophenyl chloroformate as space molecule and couping agent, respectively. The structure of copolymers was confirmed by 1H NMR, FTIR and GPC. The self-assembly of graft copolymer in the selective solvent was also investigated by 1H NMR in D2O, TEM, DLS, fluorescence spectroscopy and UV-Vis spectrometer. The micelles exhibited thermo-and pH-sensitivity. In addition, the 5-Fu-loaded micelles also showed thermo-and pH-sensitive release characteristics in the drug release system.
1.通过经典的Baeyer-Villiger氧化反应将1,4-环己二酮转化为4-羰基己内酯,进而在甲氧基聚乙二醇(MPEG)为引发剂,异辛酸亚锡(Sn(Oct)2)为催化剂的条件下,与ε-CL开环聚合,合成了两亲性悬挂侧羰基反应性官能团的聚己内酯嵌段共聚物甲氧基聚乙二醇-b-聚(4-羰基己内酯-co-己内酯)(MPEG-b-P(OPD-co-CL))。探讨了本体聚合和溶液聚合两种聚合方法对聚合物结构的影响。利用核磁共振波谱(1HNMR)、差示扫描量热法(DSC)、热重分析法(TGA)和表面接触角研究了共聚物的结构和性能。实验结果表明采用溶液聚合可以成功地合成MPEG-b-(OPD-co-CL),而本体聚合由于其反应温度较高,所得到聚合物容易发生热降解。
2.采用透析的方法,制备了侧基悬挂羰基官能团的聚己内酯嵌段共聚物(MPEG-b-P(OPD-co-CL))胶束及其包载DOX的聚合物载药胶束。探讨了胶束的制备条件和OPD含量对聚合物的临界胶束浓度(CMC)和胶束粒径大小的影响。聚合物胶束粒径大小均一,单分散性好,呈规整的球形。羰基官能团的存在增加了聚合物胶束的稳定性和聚合物载药胶束在人体生理环境(pH7.4)中的缓释效果。
3.通过透析的方法,将油酸改性过的Fe304纳米粒子载入侧基悬挂羰基官能团的MPEG-b-(OPD-co-CL)胶束中,制备了大小均一、形态呈规整球状、具有良好磁响应性和稳定性的磁性聚合物胶束,并研究了包载DOX的磁性聚合载药胶束的药物释放行为。用磁滞回线、X-射线衍射(XRD)和TGA等手段对磁性聚合物胶束和磁性载药聚合物胶束进行了表征,发现聚合物胶束对磁性粒子和DOX药物的包埋导致它们的结晶性发生改变,确证了磁性纳米粒子和DOX载入胶束核中；磁性聚合物胶束的磁含量随羰基含量的增加而增加；DOX药物的载入对磁性聚合物胶束的磁含量没有太大影响；而磁性纳米粒子的载入对聚合物载药胶束的载药量和包封率影响也不大,且有利于增加聚合物载药胶束在人体生理环境(pH7.4)中的缓释效果。
4.以羟乙肼为桥,p-氯甲酸对硝基苯酯为偶联剂,合成了主链为聚己内酯(PCL),侧链为温敏性聚(N-异丙基丙烯酰胺)(PNIPAM)的接枝共聚物PCL-g-PNIPAM.用’HNMR、红外光谱(FTIR)和凝胶渗透光谱(GPC)确证了聚合物的结构。通过透射电镜(TEM),动态光散射(DLS),荧光光谱和紫外-可见光光谱及冷冻干燥后聚合物胶束在D20中的1H NMR波谱等研究了聚合物的自组装行为,结果表明该聚合物胶束具有温度和pH敏感性。另外,包载5-Fu药物的聚合物载药胶束在药物释放体系中表现出温度和pH敏感性的释放特征。
Poly(ε-caprolactone) (PCL) have drawn considerable attention due to its excellent biodegradability, biocompatibility and drug permeability since 1990s. Especially, over the last several years, with the rapid development of nano self-assembly techniques, amphiphilic copolymer composed of hydrophobic poly(ε-caprolactone) (PCL) and hydrophilic polymers have been extensively studied in the field of drug delivery. Nowadays, the preparation of biocompatible, biodegradable and intelligent stimulus responsive drug delivery system is the current research focus and development trends. Base on this back ground and development trends, a functional poly(e-caprolactone) copolymer bearing reactive ketone groups (P(OPD-co-CL)) was developed using 2-oxepane-1,5-dione (OPD) as research starting point, and block copolymer and graft copolymer contain hydrophilic chain were also synthesized by further functional modification. All the amphiphilic polymers underwent self-assemble to form micelles and their loaded hydrophobic drug doxorubicin (DOX), oleic acid modified Fe3O4 nanoparticles and 5-fluorouracil (5-Fu) micelles were prepared by utilizing the charateristics of core. In addition, the drug release behavior of drug-loaded polymer micelles was also studied. Four sections of work were carried out as follows:
1. A amphiphilic functional block poly(ε-caprolactone) copolymer bearing ketone groups (MPEG-b-P(OPD-co-CL)) was synthesized.2-oxepane-1,5-dione (OPD) synthesized by Baeyer-Villiger oxidation of 1,4-cyclohexaedione was copolymerized withε-caprolatone (ε-CL) in which methoxy poly(ethylene glycol) (MPEG) and stannous octoate were used as initiator and catalyst, respectively. Both bulk and solution polymerization were adopted to investigate the effect of temperature on the structure of the copolymers. All the polymers were characterized by 1H-NMR, DSC, TGA and contact angle measurement. It demonstrated that the amphiphilic block copolymer with functional groups (MPEG-b-P(OPD-co-CL)) were successfully synthesized by solution polymerization. In constrast, the copolymers obtained by bulk polymerization were inclined to degrade due to the high reaction temperature.
2. Blank and DOX-loaded micelles of (MPEG-b-P(OPD-co-CL)) were prepared by a dialysis method. The effects of micelle preparation conditions and content of OPD on the critical micelle concentration (CMC) and size of polymer micelles were investigated. The polymer micelles showed uniform manodispersed spherical. The presence of ketone groups on PCL bolck is favorable to increase the thermodynamic stability of polymer micelles and sustained-release effect of drug-loaded polymer micelles in physiological environment (pH7.4).
3. With uniform size, regularly spherical shape, good magnetic responsiveness and stability of loaded oleic acid modified nano-Fe3O4 MPEG-b-(OPD-co-CL) micelles and loaded nano-Fe3O4 and DOX MPEG-b-(OPD-co-CL) micelles were carried out by a dialysis method. The drug release behavior of magnetic DOX-loaded polymer micelles was investigated. The magnetic polymer micelles and magnetic DOX-loaded polymer micelles were characterized by hysteresis loop, XRD and TGA. It was found that the polymer micelles containning oleic acid modified nano-Fe3O4 and DOX package leaded to a change in their crystalline, this result confirmed that the nano-Fe3O4 and DOX were loaded in the core of micelles; The content of nano-Fe3O4 increased with that of ketone groups increased in the hydrophobic chain, but the polymer micelles containning DOX package had little effect on the content of nano-Fe3O4. In addition, the polymer micelles containning oleic acid modified nano-Fe3O4 package also had no impact on the DLC and DEE, but are benificial to increase sustained-release effect of DOX-loaded polymer micelles in physiological environment (pH7.4).
4. The amphiphilic graft copolymers containing PCL as the hydrophobic main chain and poly(N-isopropylacrylamide) (PNIPAM) as the temperature-sensitive side chain on the side were synthesized. We use hydroxyethyl hydrazine and p-nitrophenyl chloroformate as space molecule and couping agent, respectively. The structure of copolymers was confirmed by 1H NMR, FTIR and GPC. The self-assembly of graft copolymer in the selective solvent was also investigated by 1H NMR in D2O, TEM, DLS, fluorescence spectroscopy and UV-Vis spectrometer. The micelles exhibited thermo-and pH-sensitivity. In addition, the 5-Fu-loaded micelles also showed thermo-and pH-sensitive release characteristics in the drug release system.
引文
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