酶催化两亲嵌段共聚物的合成及其纳米胶束的研究
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摘要
可生物降解性的两亲嵌段共聚物因其独特的溶液自组装性能,使其作为生物医药材料在胶束、微球、载药膜等新型给药系统中表现出优异的特性和潜在的应用价值。然而,两亲嵌段共聚物的传统的制备方法是有机金属催化剂催化的活性离子聚合法,故产物中难免会残留有毒的有机金属催化剂。作为生物医药材料,微量的有毒催化剂都会带来严重的问题。因此,寻求制备两亲嵌段共聚物的高效无毒的催化剂或环境友好的新途径具有重要的理论和实际意义。采用安全、易除去的生物催化剂的合成途径是制备两亲嵌段共聚物的重要选择之一。
本研究以脂肪酶Novozym 435为生物催化剂,分别以双端羟基的聚乙二醇(PEG,Mn=1 000, 2 000, 4 000, 6 000)和单端羟基的聚乙二醇单甲醚(MPEG,Mn=2 000, 5 000)为大分子引发剂,以甲苯为有机反应介质,在70℃下,引发ε-己内酯(ε-CL)的开环共聚合,制备三嵌段共聚物PCL-b-PEG-b-PCL和二嵌段共聚物MPEG-b-PCL。用凝胶渗透色谱法(GPC)、红外(FTIR)和核磁共振法(NMR)表征产物的分子量、分子量分布和结构;用DSC和WAXD对嵌段共聚物的热性能和结晶行为进行了表征。结果表明,制备的产物具有所设计的三嵌段和二嵌段结构;无论是PCL-b-PEG-b-PCL还是MPEG-b-PCL,共聚物的分子量都可以通过调节PEG和MPEG的分子量或反应体系中单体ε-CL和大分子底物的结构单元的摩尔比[ε-CL]/[EO]进行控制。在三嵌段共聚物的合成中,当[ε-CL]/[EO]值为2,PEG分子量从2 000增大到6 000时,PCL-b-PEG-b-PCL的分子量从11 900增加到19 000;当PEG分子量为2 000,[ε-CL]/[EO]值分别为2和4时,PCL-b-PEG-b-PCL的分子量分别为11 900和19 000;所合成的PEG分子量分别为2 000、4 000和6 000的PCL-b-PEG-b-PCL都只出现PCL链段的结晶熔融峰和结晶衍射峰,说明两端的PCL链段先结晶,PEG链段结晶受限制。在二嵌段共聚物的合成中,当[ε-CL]/[EO]值为2,MPEG分子量分别为2 000和5 000时,MPEG-b-PCL的分子量分别为10 000和11 000;当MPEG分子量为2 000,[ε-CL]/[EO]值分别为2和4时,MPEG-b-PCL的分子量分别为10 000和19 900;所合成的MPEG分子量为5 000的MPEG-b-PCL,当PCL链长小于MPEG链长时,同时出现两嵌段的结晶熔融峰和结晶衍射峰;当PCL链长大于MPEG链长时,只出现PCL链段的结晶熔融峰和衍射峰。
在此基础上,尝试分别用自乳化溶剂蒸发法、纳米沉淀技术和透析法制备了二嵌段共聚物MPEG2000-PCL1的纳米胶束,通过对纳米胶束的粒径及其粒径分布的评价,确定透析法为较适宜的制备方法。采用透析法制备了不同结构和组成的嵌段共聚物的纳米胶束,进而用粒径分析仪测定了它们的粒径及其粒径分布,用TEM观察了胶束的形态结构,用芘荧光探针技术测定嵌段共聚物的临界聚集浓度(CAC),用紫外分光光度计法测定了嵌段共聚物的临界聚沉浓度(CFPT)。研究结果表明,两亲嵌段共聚物纳米胶束粒子具有明显的球形核壳结构,三嵌段共聚物和二嵌段共聚物纳米胶束的粒径分别在80~160 nm和45~90 nm之间,三嵌段共聚物纳米胶束粒径比二嵌段的明显增大,且随着嵌段共聚物分子量增大和疏水链段PCL增长,纳米胶束的粒径同时增大;嵌段共聚物的CAC值均很小,在1.62×10-3 g/L以内,且随着嵌段共聚物中亲水嵌段PEG和MPEG的质量分数下降到10.5%,CAC值减小到1.12×10-3 g/L,而嵌段共聚物的三嵌段或二嵌段结构对共聚物的CAC影响不大;随着嵌段共聚物中亲水嵌段PEG和MPEG的质量分数增大,两亲三嵌段和二嵌段共聚物的CFPT值增大,纳米胶束的稳定性增强。
Amphiphilic copolymers contain both hydrophilic and oleophilic chemical structures in their molecular chain segments, which provides their unique self-assembly behaviors in solutions and makes them especially suitable to be used as pharmaceutical carriers in micelles, microspheres, drug loaded membranes and other new-type drug delivery system. At present, block copolymers containing PCL and PEG chains are mainly prepared by active ionic polymerization using traditional chemical catalysts, some toxic organometallic compounds. As in biomedical materials, even a tiny quantity of catalyst remains can cause serious toxicity problems. Therefore, it is of vital importance to find some highly efficient and non-toxic catalysts. One of a possible ways to solve this problem is to use enzyme preparations instead of chemical catalysts.
In this work, amphiphilic triblock biodegradable PCL-b-PEG-b-PCL and diblock copolymers MPEG-b-PCL prepared by the ring-opening polymerization ofε-caprolactone (ε-CL) in organic medium toluene, at 70℃, employing lipase Novozym 435 as catalyst with double-hydroxyl capped poly (ethylene glycol) (PEG, Mn=1 000, 2 000, 4 000, 6 000) or monomethoxy polyethylene glycol (MPEG, Mn=2 000, 5 000) as macromolecular initiator, respectively. The prepared copolymers were characterized by GPC, FTIR, 1H NMR, 13C NMR, DSC and WAXD. The results show that the production possessed the expected triblock or diblock structure containing both poly (ε-caprolactone) and poly (ethylene oxide) chains. Neither PCL-b-PEG-b-PCL or MPEG-b-PCL the molecular weight can be well controlled by adjusting the feeding molar ratio ofε-CL to EO ([ε-CL]/[EO]) and the molecular weight of the macromolecular initiators to PEG or MPEG. When [ε-CL]/[EO] holding with 2, the molecular weight of PEG got from 2 000 to 6 000, the molecular weight of the triblock copolymers PCL-b-PEG-b-PCL got from 11 900 to 19 000. But keeping the molecular weight of PEG with 2 000, [ε-CL]/[EO] with 2 and 4, the molecular weight of PCL-b-PEG-b-PCL were 11 900 and 19 000. When triblock copolymers PCL-b-PEG-b-PCL with the molecular weight of PEG got from 2 000 to 6 000, the crystallization and melting peaks and crystalline diffraction peaks which belong to PCL block, which indicated that PCL crystalized first and PEG was restricted. When [ε-CL]/[EO] holding with 2, the molecular weight of MPEG with 2 000 or 5 000, the molecular weight of MPEG-b-PCL were 10 000 and 11,000. But keeping the molecular weight of MPEG with 2 000, [ε-CL]/[EO] with 2 and 4, the molecular weight MPEG-b-PCL were 10 000 and 19 900. Diblock copolymers MPEG-b-PCL with the molecular weight of MPEG at 5 000, when MPEG was longer than PCL, the crystallization and melting peaks and crystalline diffraction peaks belong to MPEG and PCL, respectively. But PCL longer, the crystallization and melting peaks and crystalline diffraction peaks which belong to PCL block.
On the basis, we prepared the diblock copolymer MPEG2000-PCL1 nano-micelles by the methods of self-emulsification diffusion method, nano meter precipitation method and dialysis method, according to micellar particle size and distribution, make sure dialysis method was the most suitable. Moreover, the different compositions of block copolymers were prepared by dialysis method. Empolying particle size analyzer to measurement micellars particle size and distribution, and TEM to study micellars morphological characteristics. The critical association concentrations (CACs) were determined by fluorescence technique using pyrene as probe, and the critical flocculation point (CFPTs) were determined by ultraviolet-visible pectrophotometer. The results showed that, nano-micelles possessed a core-shell structure, regularly spherical in shape. The nano-micelles made from triblock copolymers and diblock copolymers particle size were between 80~160 nm and 45~90 nm, respectively. The CAC were all less then 1.62×10-3 g/L, with lower mass fraction of PEG or MPEG to 10.5%, the CAC decreased to 1.12×10-3 g/L. With higher mass fraction of PEG or MPEG, the CFPTs of block copolymers were increased, improved the nano-micelles stability.
本研究以脂肪酶Novozym 435为生物催化剂,分别以双端羟基的聚乙二醇(PEG,Mn=1 000, 2 000, 4 000, 6 000)和单端羟基的聚乙二醇单甲醚(MPEG,Mn=2 000, 5 000)为大分子引发剂,以甲苯为有机反应介质,在70℃下,引发ε-己内酯(ε-CL)的开环共聚合,制备三嵌段共聚物PCL-b-PEG-b-PCL和二嵌段共聚物MPEG-b-PCL。用凝胶渗透色谱法(GPC)、红外(FTIR)和核磁共振法(NMR)表征产物的分子量、分子量分布和结构;用DSC和WAXD对嵌段共聚物的热性能和结晶行为进行了表征。结果表明,制备的产物具有所设计的三嵌段和二嵌段结构;无论是PCL-b-PEG-b-PCL还是MPEG-b-PCL,共聚物的分子量都可以通过调节PEG和MPEG的分子量或反应体系中单体ε-CL和大分子底物的结构单元的摩尔比[ε-CL]/[EO]进行控制。在三嵌段共聚物的合成中,当[ε-CL]/[EO]值为2,PEG分子量从2 000增大到6 000时,PCL-b-PEG-b-PCL的分子量从11 900增加到19 000;当PEG分子量为2 000,[ε-CL]/[EO]值分别为2和4时,PCL-b-PEG-b-PCL的分子量分别为11 900和19 000;所合成的PEG分子量分别为2 000、4 000和6 000的PCL-b-PEG-b-PCL都只出现PCL链段的结晶熔融峰和结晶衍射峰,说明两端的PCL链段先结晶,PEG链段结晶受限制。在二嵌段共聚物的合成中,当[ε-CL]/[EO]值为2,MPEG分子量分别为2 000和5 000时,MPEG-b-PCL的分子量分别为10 000和11 000;当MPEG分子量为2 000,[ε-CL]/[EO]值分别为2和4时,MPEG-b-PCL的分子量分别为10 000和19 900;所合成的MPEG分子量为5 000的MPEG-b-PCL,当PCL链长小于MPEG链长时,同时出现两嵌段的结晶熔融峰和结晶衍射峰;当PCL链长大于MPEG链长时,只出现PCL链段的结晶熔融峰和衍射峰。
在此基础上,尝试分别用自乳化溶剂蒸发法、纳米沉淀技术和透析法制备了二嵌段共聚物MPEG2000-PCL1的纳米胶束,通过对纳米胶束的粒径及其粒径分布的评价,确定透析法为较适宜的制备方法。采用透析法制备了不同结构和组成的嵌段共聚物的纳米胶束,进而用粒径分析仪测定了它们的粒径及其粒径分布,用TEM观察了胶束的形态结构,用芘荧光探针技术测定嵌段共聚物的临界聚集浓度(CAC),用紫外分光光度计法测定了嵌段共聚物的临界聚沉浓度(CFPT)。研究结果表明,两亲嵌段共聚物纳米胶束粒子具有明显的球形核壳结构,三嵌段共聚物和二嵌段共聚物纳米胶束的粒径分别在80~160 nm和45~90 nm之间,三嵌段共聚物纳米胶束粒径比二嵌段的明显增大,且随着嵌段共聚物分子量增大和疏水链段PCL增长,纳米胶束的粒径同时增大;嵌段共聚物的CAC值均很小,在1.62×10-3 g/L以内,且随着嵌段共聚物中亲水嵌段PEG和MPEG的质量分数下降到10.5%,CAC值减小到1.12×10-3 g/L,而嵌段共聚物的三嵌段或二嵌段结构对共聚物的CAC影响不大;随着嵌段共聚物中亲水嵌段PEG和MPEG的质量分数增大,两亲三嵌段和二嵌段共聚物的CFPT值增大,纳米胶束的稳定性增强。
Amphiphilic copolymers contain both hydrophilic and oleophilic chemical structures in their molecular chain segments, which provides their unique self-assembly behaviors in solutions and makes them especially suitable to be used as pharmaceutical carriers in micelles, microspheres, drug loaded membranes and other new-type drug delivery system. At present, block copolymers containing PCL and PEG chains are mainly prepared by active ionic polymerization using traditional chemical catalysts, some toxic organometallic compounds. As in biomedical materials, even a tiny quantity of catalyst remains can cause serious toxicity problems. Therefore, it is of vital importance to find some highly efficient and non-toxic catalysts. One of a possible ways to solve this problem is to use enzyme preparations instead of chemical catalysts.
In this work, amphiphilic triblock biodegradable PCL-b-PEG-b-PCL and diblock copolymers MPEG-b-PCL prepared by the ring-opening polymerization ofε-caprolactone (ε-CL) in organic medium toluene, at 70℃, employing lipase Novozym 435 as catalyst with double-hydroxyl capped poly (ethylene glycol) (PEG, Mn=1 000, 2 000, 4 000, 6 000) or monomethoxy polyethylene glycol (MPEG, Mn=2 000, 5 000) as macromolecular initiator, respectively. The prepared copolymers were characterized by GPC, FTIR, 1H NMR, 13C NMR, DSC and WAXD. The results show that the production possessed the expected triblock or diblock structure containing both poly (ε-caprolactone) and poly (ethylene oxide) chains. Neither PCL-b-PEG-b-PCL or MPEG-b-PCL the molecular weight can be well controlled by adjusting the feeding molar ratio ofε-CL to EO ([ε-CL]/[EO]) and the molecular weight of the macromolecular initiators to PEG or MPEG. When [ε-CL]/[EO] holding with 2, the molecular weight of PEG got from 2 000 to 6 000, the molecular weight of the triblock copolymers PCL-b-PEG-b-PCL got from 11 900 to 19 000. But keeping the molecular weight of PEG with 2 000, [ε-CL]/[EO] with 2 and 4, the molecular weight of PCL-b-PEG-b-PCL were 11 900 and 19 000. When triblock copolymers PCL-b-PEG-b-PCL with the molecular weight of PEG got from 2 000 to 6 000, the crystallization and melting peaks and crystalline diffraction peaks which belong to PCL block, which indicated that PCL crystalized first and PEG was restricted. When [ε-CL]/[EO] holding with 2, the molecular weight of MPEG with 2 000 or 5 000, the molecular weight of MPEG-b-PCL were 10 000 and 11,000. But keeping the molecular weight of MPEG with 2 000, [ε-CL]/[EO] with 2 and 4, the molecular weight MPEG-b-PCL were 10 000 and 19 900. Diblock copolymers MPEG-b-PCL with the molecular weight of MPEG at 5 000, when MPEG was longer than PCL, the crystallization and melting peaks and crystalline diffraction peaks belong to MPEG and PCL, respectively. But PCL longer, the crystallization and melting peaks and crystalline diffraction peaks which belong to PCL block.
On the basis, we prepared the diblock copolymer MPEG2000-PCL1 nano-micelles by the methods of self-emulsification diffusion method, nano meter precipitation method and dialysis method, according to micellar particle size and distribution, make sure dialysis method was the most suitable. Moreover, the different compositions of block copolymers were prepared by dialysis method. Empolying particle size analyzer to measurement micellars particle size and distribution, and TEM to study micellars morphological characteristics. The critical association concentrations (CACs) were determined by fluorescence technique using pyrene as probe, and the critical flocculation point (CFPTs) were determined by ultraviolet-visible pectrophotometer. The results showed that, nano-micelles possessed a core-shell structure, regularly spherical in shape. The nano-micelles made from triblock copolymers and diblock copolymers particle size were between 80~160 nm and 45~90 nm, respectively. The CAC were all less then 1.62×10-3 g/L, with lower mass fraction of PEG or MPEG to 10.5%, the CAC decreased to 1.12×10-3 g/L. With higher mass fraction of PEG or MPEG, the CFPTs of block copolymers were increased, improved the nano-micelles stability.
引文
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