可逆交联、温度敏感的聚合物囊泡用于蛋白质的可控释放
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摘要
聚合物囊泡载体体系在生物医学和药物控释领域的应用已经引起科学家们的广泛的关注。本论文中,作者主要设计合成了一系列结构明确的,三嵌段聚合物PEG-PAA-PNIPAM,研究了其囊泡的温度敏感性和可逆交联,并探索了该可逆交联的温度敏感的聚合物囊泡用于蛋白质药物的细胞内释放。
(1)以大分子PEG-DMP作为链引发剂,通过序贯可逆加成-断裂链转移自由基聚合方法得到具有温度敏感的聚乙二醇-b-聚丙烯酸-b-聚-N-异丙基丙烯酰胺三嵌段聚合物(PEG-PAA-PNIPAM)。嵌段聚合物中聚乙二醇的分子量为5000 Da﹑聚丙烯酸分子量为350~1450 Da、聚丙烯酰胺分子量为11000~39000 Da。该嵌段共聚物在室温下易溶于水,当水溶液升温到37oC以上,溶液能迅速自组装形成纳米囊泡(粒径大约220 nm)。通过共聚焦光散射激光显微镜(CSLM)和静态激光光散射(SLS)方法证实了其囊泡结构。囊泡的粒径大小和粒径分布取决于聚合物浓度﹑聚丙烯酰胺的分子量﹑溶液平衡时间和晃动程度。有趣的是,用含有二硫键的胱胺以碳二亚胺化学法对囊泡进行化学交联,可以得到界面交联的囊泡。通过稀释﹑加入有机溶剂﹑改变盐浓度和改变溶液温度的方法,证实了交联后囊泡的稳定性可以显著增加。而在模拟细胞内的还原环境时,交联会因胱胺的二硫键断裂而快速降解,聚合物囊泡溶解。FITC-葡聚糖作为模拟蛋白质,能被高效地包裹到囊泡内。通过体外释放研究,即使温度降到LCST以下(如20oC),大部分FITC-葡聚糖仍保留在交联的囊泡内。但是,在加入10 mM的二硫苏糖醇时,大部分FITC-葡聚糖从已解除交联的囊泡中释放出来。这些可逆交联温度敏感的囊泡也许可以作为智能型载体,应用于生物药剂的细胞内刺激释放,例如有效控释pDNA,siRNA,蛋白质药物。
(2)三嵌段聚合物PEG-PAA-PNIPAM的LCST受嵌段的比例、盐浓度、溶液pH的影响,可在28oC至50oC之间调节。通过设计合适的嵌段比例,使嵌段聚合物的LCST在PBS中可从38oC至43oC之间,目的是使上述聚合物囊泡能在解交联后在体温下溶解,从而释放出其包裹的药物。为此设计得到了PEG113-PAA9-PNIPAM107,PEG113-PAA24-PNIAPM193,和PEG113-PAA35-PNIPAM290。它们的LCST均在38-42oC之间。FITC-BSA作为模拟蛋白质,能被高效地包裹到该囊泡内。该界面交联的温度敏感的聚合物囊泡对其他研究的蛋白质(如细胞色素C,溶菌酶,卵清白蛋白和免疫球蛋白)的包裹效率略低,但也在35-50%,载药率为4-50wt.%。通过体外释放研究(37oC),在加入10 mM的二硫苏糖醇时,大部分蛋白质(80%)从交联的囊泡中释放出来。而没有加入10 mM二硫苏糖醇时,大部分蛋白质(80-85%)在8小时后能仍保留在囊泡内。体外细胞实验结果说明,这种蛋白质载体能有效将蛋白质运输到细胞内。所以,这些可逆交联温度敏感的囊泡可能克服现有技术的缺陷,提高囊泡对小分子药物、大分子药物以及探针分子的包载效率,提高囊泡在体内血液中循环的稳定性,提高囊泡被肿瘤细胞内吞的效率,从而提高药物的生物利用度。
Polymersomes have attracted significant attentions for biomedical applications and drug delivery systems. In this thesis, we have synthesized a series of well defined block copolymer of PEG-PAA-PNIPAM, studied their thermal sensitivity during the formation of the polymersomes and the reversible crosslinking, and explored the encapsulation of the proteins into the polymersomes and the intracellular release of the proteins.
(1) Water-soluble temperature responsive triblock copolymers, poly(ethylene oxide)-b-poly(acrylic acid)-b-poly(N-isopropylacrylamide) (PEO-PAA-PNIPAM), were prepared in one pot by sequential reversible addition–fragmentation chain-transfer (RAFT) polymerization using a PEO-trithiocarbonate (PEO-S-1-dodecyl-S-(R,R- dimethyl-R-aceticacid) trithiocarbonate) as a macro chain transfer agent. The block copolymers have Mn PEO of 5 kDa, Mn PAA of 0.35-1.45 kDa, and Mn PNIPAM varying from 11-39 kDa. They were freely soluble in water as unimers at room temperature, but quickly self-assembled into nano-sized vesicles (about 220 nm) when raising the solution temperature to 37 oC. The vesicular structure was confirmed by confocal scanning laser microscope (CSLM) and static light scattering (SLS) measurements. The size and size distribution of the polymersomes depended on solution concentration, molecular weight of PNIPAM, the equilibrium time and shaking. Interestingly, thus formed vesicles could be readily cross-linked at the interface using cysteamine via the carbodiimide chemistry. The crosslinked polymersomes, while showed remarkable stability against dilution, organic solvent, high salt conditions and change of temperature in water, were otherwise rapidly dissociated under reductive conditions mimicking intracellular environment. Notably, FITC-dextran were shown to be encapsulated into the polymersomes with an unprecedently high loading efficiency. The release studies showed that most FITC-dextran was retained within the crosslinked polymersomes after lowering the temperature to 20°C. However, in the presence of 10 mM dithiothreitol (DTT), fast release of FITC-dextran was achieved. These reversibly crosslinked temperature responsive nano-sized polymersomes are highly promising as smart carriers for triggered intracellular delivery of biopharmaceutics such as pDNA, siRNA, pharmaceutical proteins and peptides.
(2) The LCST of the above mentioned triblock copolymer PEO-PAA-PNIPAM can be adjusted from 28 oC to 50 oC by changing the block ratio, salt concentration, and pH. We designed copolymers with suitable proportion, in order to have their LCST in between 38 oC and 43 oC, so that after de-crosslinking the copolymer can dissolve in PBS molecularly. Notably, FITC-BSA was efficiently encapsulated into the polymersomes. For other proteins studied here, they all were encapsulated into the polymersomes with loading efficiency of 35-50%, and loading content of 4-50 wt.%. In vitro release studies showed that (37 o C in PB), in the presence of 10 mM dithiothreitol (DTT), fast release of FITC-BSA (80 % released within 7-8 hr) was achieved. However, without 10 mM DTT, most of the protein (80-85%) remains within the polymersomes after 8 hr. Cell experiments demonstrated that the proteins can effectively be transported into the cells. Thus these reversible cross-linked temperature-sensitive polymersomes can overcome the shortcomings of existing technologies, which can enhance loading efficiency of small molecule drugs, macromolecular drugs and probe molecule, enhance stability of polymersomes in the blood circulation, and enhance the endocytosis efficiency, so it can increase the bioavailability.
(1)以大分子PEG-DMP作为链引发剂,通过序贯可逆加成-断裂链转移自由基聚合方法得到具有温度敏感的聚乙二醇-b-聚丙烯酸-b-聚-N-异丙基丙烯酰胺三嵌段聚合物(PEG-PAA-PNIPAM)。嵌段聚合物中聚乙二醇的分子量为5000 Da﹑聚丙烯酸分子量为350~1450 Da、聚丙烯酰胺分子量为11000~39000 Da。该嵌段共聚物在室温下易溶于水,当水溶液升温到37oC以上,溶液能迅速自组装形成纳米囊泡(粒径大约220 nm)。通过共聚焦光散射激光显微镜(CSLM)和静态激光光散射(SLS)方法证实了其囊泡结构。囊泡的粒径大小和粒径分布取决于聚合物浓度﹑聚丙烯酰胺的分子量﹑溶液平衡时间和晃动程度。有趣的是,用含有二硫键的胱胺以碳二亚胺化学法对囊泡进行化学交联,可以得到界面交联的囊泡。通过稀释﹑加入有机溶剂﹑改变盐浓度和改变溶液温度的方法,证实了交联后囊泡的稳定性可以显著增加。而在模拟细胞内的还原环境时,交联会因胱胺的二硫键断裂而快速降解,聚合物囊泡溶解。FITC-葡聚糖作为模拟蛋白质,能被高效地包裹到囊泡内。通过体外释放研究,即使温度降到LCST以下(如20oC),大部分FITC-葡聚糖仍保留在交联的囊泡内。但是,在加入10 mM的二硫苏糖醇时,大部分FITC-葡聚糖从已解除交联的囊泡中释放出来。这些可逆交联温度敏感的囊泡也许可以作为智能型载体,应用于生物药剂的细胞内刺激释放,例如有效控释pDNA,siRNA,蛋白质药物。
(2)三嵌段聚合物PEG-PAA-PNIPAM的LCST受嵌段的比例、盐浓度、溶液pH的影响,可在28oC至50oC之间调节。通过设计合适的嵌段比例,使嵌段聚合物的LCST在PBS中可从38oC至43oC之间,目的是使上述聚合物囊泡能在解交联后在体温下溶解,从而释放出其包裹的药物。为此设计得到了PEG113-PAA9-PNIPAM107,PEG113-PAA24-PNIAPM193,和PEG113-PAA35-PNIPAM290。它们的LCST均在38-42oC之间。FITC-BSA作为模拟蛋白质,能被高效地包裹到该囊泡内。该界面交联的温度敏感的聚合物囊泡对其他研究的蛋白质(如细胞色素C,溶菌酶,卵清白蛋白和免疫球蛋白)的包裹效率略低,但也在35-50%,载药率为4-50wt.%。通过体外释放研究(37oC),在加入10 mM的二硫苏糖醇时,大部分蛋白质(80%)从交联的囊泡中释放出来。而没有加入10 mM二硫苏糖醇时,大部分蛋白质(80-85%)在8小时后能仍保留在囊泡内。体外细胞实验结果说明,这种蛋白质载体能有效将蛋白质运输到细胞内。所以,这些可逆交联温度敏感的囊泡可能克服现有技术的缺陷,提高囊泡对小分子药物、大分子药物以及探针分子的包载效率,提高囊泡在体内血液中循环的稳定性,提高囊泡被肿瘤细胞内吞的效率,从而提高药物的生物利用度。
Polymersomes have attracted significant attentions for biomedical applications and drug delivery systems. In this thesis, we have synthesized a series of well defined block copolymer of PEG-PAA-PNIPAM, studied their thermal sensitivity during the formation of the polymersomes and the reversible crosslinking, and explored the encapsulation of the proteins into the polymersomes and the intracellular release of the proteins.
(1) Water-soluble temperature responsive triblock copolymers, poly(ethylene oxide)-b-poly(acrylic acid)-b-poly(N-isopropylacrylamide) (PEO-PAA-PNIPAM), were prepared in one pot by sequential reversible addition–fragmentation chain-transfer (RAFT) polymerization using a PEO-trithiocarbonate (PEO-S-1-dodecyl-S-(R,R- dimethyl-R-aceticacid) trithiocarbonate) as a macro chain transfer agent. The block copolymers have Mn PEO of 5 kDa, Mn PAA of 0.35-1.45 kDa, and Mn PNIPAM varying from 11-39 kDa. They were freely soluble in water as unimers at room temperature, but quickly self-assembled into nano-sized vesicles (about 220 nm) when raising the solution temperature to 37 oC. The vesicular structure was confirmed by confocal scanning laser microscope (CSLM) and static light scattering (SLS) measurements. The size and size distribution of the polymersomes depended on solution concentration, molecular weight of PNIPAM, the equilibrium time and shaking. Interestingly, thus formed vesicles could be readily cross-linked at the interface using cysteamine via the carbodiimide chemistry. The crosslinked polymersomes, while showed remarkable stability against dilution, organic solvent, high salt conditions and change of temperature in water, were otherwise rapidly dissociated under reductive conditions mimicking intracellular environment. Notably, FITC-dextran were shown to be encapsulated into the polymersomes with an unprecedently high loading efficiency. The release studies showed that most FITC-dextran was retained within the crosslinked polymersomes after lowering the temperature to 20°C. However, in the presence of 10 mM dithiothreitol (DTT), fast release of FITC-dextran was achieved. These reversibly crosslinked temperature responsive nano-sized polymersomes are highly promising as smart carriers for triggered intracellular delivery of biopharmaceutics such as pDNA, siRNA, pharmaceutical proteins and peptides.
(2) The LCST of the above mentioned triblock copolymer PEO-PAA-PNIPAM can be adjusted from 28 oC to 50 oC by changing the block ratio, salt concentration, and pH. We designed copolymers with suitable proportion, in order to have their LCST in between 38 oC and 43 oC, so that after de-crosslinking the copolymer can dissolve in PBS molecularly. Notably, FITC-BSA was efficiently encapsulated into the polymersomes. For other proteins studied here, they all were encapsulated into the polymersomes with loading efficiency of 35-50%, and loading content of 4-50 wt.%. In vitro release studies showed that (37 o C in PB), in the presence of 10 mM dithiothreitol (DTT), fast release of FITC-BSA (80 % released within 7-8 hr) was achieved. However, without 10 mM DTT, most of the protein (80-85%) remains within the polymersomes after 8 hr. Cell experiments demonstrated that the proteins can effectively be transported into the cells. Thus these reversible cross-linked temperature-sensitive polymersomes can overcome the shortcomings of existing technologies, which can enhance loading efficiency of small molecule drugs, macromolecular drugs and probe molecule, enhance stability of polymersomes in the blood circulation, and enhance the endocytosis efficiency, so it can increase the bioavailability.
引文
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