细胞膜仿生聚合物囊泡作为药物微载体的研究
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摘要
具有独特空腔结构的聚合物囊泡由于在药物与基因传递、人工细胞模型、生物微反应器等多方面的潜在应用价值,已经吸引越来越多的关注。特别是利用囊泡作为各种药剂分子的载体展现出光明的应用前景。本论文通过合成基于磷酸胆碱的双嵌段共聚物和研究共聚物在水溶液中的组装行为,致力于构建新型的细胞膜仿生聚合物囊泡。并探索了这种具有良好生物相容性的聚合物囊泡作为药物微载体的潜在应用。研究围绕着细胞膜仿生囊泡构建、囊泡的形成机理以及降解诱导的可控药物释放,分别展开了以下工作：
1.利用原子转移自由基聚合(ATRP)技术,合成了两亲双嵌段共聚物聚乳酸-b-聚磷酸胆碱(PLA-b-PMPC)。通过研究其在水溶液中的组装行为,发现不同亲疏水比例的PLA-b-PMPC可以组装为囊泡和胶束。通过设计PMPC嵌段的亲水分数fPC爪为50%左右,采用溶剂注射法获得了微米尺寸和纳米尺寸的囊泡。发现亲水分数fPC在囊泡的尺寸和形貌两方面起到控制作用。细胞膜仿生界面、空心结构和可控微米尺寸实现了PLA-b-PMPC囊泡对生物活细胞的结构模拟。这种可降解细胞膜仿生囊泡为开发新型生物相容性药物微载体和人工细胞模型提供了可能。
2.以巯基磷酸胆碱修饰的量子点(PC@QD)为亲水分子模型,探索了PLA-b-PMPC囊泡对亲水药物的包封效率。透射电子显微镜、流式细胞仪测试表明聚合物囊泡能够有效地将亲水量子点包封在其亲水空腔内。说明这种细胞膜仿生的聚合物囊泡可以作为亲水药物的有效载体。此外,TEM观察发现还有一部分PC@QD沿着囊泡壁的内外表面均匀分布。我们认为这种特殊吸附是由于量子点表面上和囊泡内外表面上的磷酸胆碱分子间形成的静电离子对造成。通过包封实验结果和量子点在囊泡壁上的特殊吸附,我们提出了囊泡的形成机理。认为囊泡在形成的过程中,两亲双嵌段共聚物首先在水溶液中形成球形胶束,然后再转变为蠕虫状和圆盘状胶束,最后卷曲闭合形成聚合物囊泡。
3.制备了可降解性细胞膜仿生囊泡作为抗癌药物纳米载体。首先成功地将亲水和疏水抗癌药物分别载入囊泡的亲水空腔和疏水膜中。体外释放试验表明药物的释放是高度pH依赖性的,对比于生理条件pH7.4,在酸性pH5.0条件下药物释放速度更快。进一步发现,在相同的pH条件下,亲水药物的释放速度要比疏水药物快。这种pH依赖性的释放速率归功于PLA-b-PMPC囊泡的降解。酸性pH加速囊泡的水解并诱导囊泡转变为胶束形貌,并释放负载药物。细胞实验表明,载药囊泡能够快速被肝癌细胞内吞,内质溶酶体的酸性环境会加速载药囊泡的降解并增强药物在细胞质内的释放。
4.聚乙二醇PEG和聚磷酸胆碱PMPC都是具有良好生物相容性的聚合物。以此为出发点,合成了全亲水的双嵌段共聚物PEG-b-PMPC.利用a-环糊精与PEG-b-PMPC的超分子嵌套络合作用,在水溶液中不引入有机溶剂直接构建了一种新型的PEG-b-PMPC/α-CD细胞膜仿生囊泡。由于构建囊泡的材料全都是亲水的低细胞毒性生物材料,细胞活性评价结果表明PEG-b-PMPC/α-CD囊泡具有十分优异的生物相容性,可作为亲水抗癌药物的载体应用于药物传递领域。亲水抗癌药物阿霉素DOX·HCl能被成功地包封进囊泡的亲水内腔,载药量和载药效率分别为10.3%和30%。细胞膜仿生囊泡包载药物后能显著降低自由药物的毒性。荧光显微镜表明,载药囊泡同时能够有效地将药物传送到肝癌细胞内。
Polymersomes, self-assembled vesicles of amphiphilic copolymers, usually possess an aqueous interior separated from the outside by the hydrophobic membrane with both external and internal surfaces formed by hydrophilic shells. In recent years, this unique morphology has attracted considerable attention due to their potential applications in biomedicine as drug and gene delivery carriers, artificial cells and bioreactors. However, the utilization of the polymersome as carriers for various therapeutic agents may be the most promising. In this paper, we synthetized diblock copolymers based on phosphorylcholine molecules and studied their self-assembly behavior to construct cell membrane mimetic polymersomes. The potential application of such biocompatible polymersomes as durg carriers was also explored. The main work in this paper foucses on the construction and the formation mechanism of cell-membrane mimetic polymersomes, and the degradation-induced controllable release:
(1) The poly(D,L-lactide)-block-poly(2-methacryloyloxyethyl phosphorylcholine)(PLA-b-PMPC) was specially designed to develop biomimetic giant polymersomes and nano-sized polymersomes via a simple spontaneous assemble in aqueous solution. The weight fraction of the hydrophilic PMPC block (fPC) was proved to play an important role in the size and morphology control of the self-assembled aggregates. The large polymersomes with controlled micro-meter size and biomimetic PMPC corona have great potential as artificial cell models. The nano-sized polymersomes can be used as drug carriers for cancer therapy.
(2) For polymersomes to achieve their potential as effective delivery vehicles, they must efficiently encapsulate therapeutic agents into either the aqueous interior or the hydrophobic membrane. Cell membrane-mimetic polymersomes were prepared from amphiphilic PLA-b-PMPC diblock copolymers and were used as encapsulation devices for water-soluble molecules. Thioalkylated zwitterionic phosphorylcholine protected quantum dots (PC@QDs) were chosen as hydrophilic model substrates and successfully encapsulated into the aqueous polymersome interior, as evidenced by transmission electron microscopy (TEM) and flow cytometry. In addition, we also found a fraction of the PC@QDs was bounded to both the external and internal surfaces of the polymersome. This interesting immobilization might be due to the ion-pair interactions between the phosphorylcholine groups on the PC@QDs and polymersomes. The experimental encapsulation results support amechanism of PLA-b-PMPC polymersome formation, in which PLA-b-PMPC copolymer chains first form spherical micelles, then worm-like micelles, and finally disk-like micelles which close up to form polymersomes.
(3) Nano-sized biocompatible and biodegradable polymersomes were prepared based on PLA-b-PMPC diblock copolymers and applied for the release anti-cancer drugs. Hydrophobic doxorubicin (DOX) and hydrophilic doxorubicin hydrochloride (DOX·HCl) were successfully loaded into the polymersome membrane and polymersome interior, respectively. The in vitro release studies demonstrated that the release of DOX and DOX·HCl from polymersomes was highly pH-dependent, i.e. significantly faster drug release at mildly acidic pH of5.0compared to physiological pH7.4. Furthermore, DOX·HCl-loaded polymersomes exhibited faster drug release than DOX-loaded polymersomes under the same pH conditions. The highly pH-depended release behavior was attributed to the hydrolysis of PLA-b-PMPC, which would result in morphological transformation from polymersome to micelle with a triggered release of the encapsulated drugs. The drug-loaded polymersomes were shown to rapidly enter HepG2cells, localize in their endosome/lysosomes with acidic pH environment and display enhanced intracellular release of the drugs into the cytosol. These biocompatible and acid pH-sensitive polymersomes might have great potential for cancer therapy.
(4) PEO and PMPC are biocompatible polymers that have delivered clinically proven benefits in various biomedical applications. Biocompatible polymer polymersomes were prepared on basis of the inclusion complexation between α-cyclodextrins (α-CDs) and double-hydrophilic PEO-b-PMPC in aqueous media without using organic solvent. The supramolecular structure of the nano-sized vesicles was demonstrated by transmission electron microscopy (TEM), atomic force microscopy (AFM) and dynamic light scattering (DLS). The biocompatibility of PEO-b-PMPC block copolymers and PEO-b-PMPC/a-CDs vesicles were studied by cell viability test, and the results revealed that both of them showed excellent cytocompatibility. Hydrophilic doxorubicin (DOX·HCl) was successfully loaded into the vesicle with loading content of10.3%and loading efficiency of30%. The DOX·HCl loaded vesicles showed lower cytotoxicity than free drugs, and could efficiently deliver and release the drug into HepG2cells as confirmed by fluorescence microscope (FM). With these properties, the polymer vesicles are attractive as drug carriers for pharmaceutical applications.
1.利用原子转移自由基聚合(ATRP)技术,合成了两亲双嵌段共聚物聚乳酸-b-聚磷酸胆碱(PLA-b-PMPC)。通过研究其在水溶液中的组装行为,发现不同亲疏水比例的PLA-b-PMPC可以组装为囊泡和胶束。通过设计PMPC嵌段的亲水分数fPC爪为50%左右,采用溶剂注射法获得了微米尺寸和纳米尺寸的囊泡。发现亲水分数fPC在囊泡的尺寸和形貌两方面起到控制作用。细胞膜仿生界面、空心结构和可控微米尺寸实现了PLA-b-PMPC囊泡对生物活细胞的结构模拟。这种可降解细胞膜仿生囊泡为开发新型生物相容性药物微载体和人工细胞模型提供了可能。
2.以巯基磷酸胆碱修饰的量子点(PC@QD)为亲水分子模型,探索了PLA-b-PMPC囊泡对亲水药物的包封效率。透射电子显微镜、流式细胞仪测试表明聚合物囊泡能够有效地将亲水量子点包封在其亲水空腔内。说明这种细胞膜仿生的聚合物囊泡可以作为亲水药物的有效载体。此外,TEM观察发现还有一部分PC@QD沿着囊泡壁的内外表面均匀分布。我们认为这种特殊吸附是由于量子点表面上和囊泡内外表面上的磷酸胆碱分子间形成的静电离子对造成。通过包封实验结果和量子点在囊泡壁上的特殊吸附,我们提出了囊泡的形成机理。认为囊泡在形成的过程中,两亲双嵌段共聚物首先在水溶液中形成球形胶束,然后再转变为蠕虫状和圆盘状胶束,最后卷曲闭合形成聚合物囊泡。
3.制备了可降解性细胞膜仿生囊泡作为抗癌药物纳米载体。首先成功地将亲水和疏水抗癌药物分别载入囊泡的亲水空腔和疏水膜中。体外释放试验表明药物的释放是高度pH依赖性的,对比于生理条件pH7.4,在酸性pH5.0条件下药物释放速度更快。进一步发现,在相同的pH条件下,亲水药物的释放速度要比疏水药物快。这种pH依赖性的释放速率归功于PLA-b-PMPC囊泡的降解。酸性pH加速囊泡的水解并诱导囊泡转变为胶束形貌,并释放负载药物。细胞实验表明,载药囊泡能够快速被肝癌细胞内吞,内质溶酶体的酸性环境会加速载药囊泡的降解并增强药物在细胞质内的释放。
4.聚乙二醇PEG和聚磷酸胆碱PMPC都是具有良好生物相容性的聚合物。以此为出发点,合成了全亲水的双嵌段共聚物PEG-b-PMPC.利用a-环糊精与PEG-b-PMPC的超分子嵌套络合作用,在水溶液中不引入有机溶剂直接构建了一种新型的PEG-b-PMPC/α-CD细胞膜仿生囊泡。由于构建囊泡的材料全都是亲水的低细胞毒性生物材料,细胞活性评价结果表明PEG-b-PMPC/α-CD囊泡具有十分优异的生物相容性,可作为亲水抗癌药物的载体应用于药物传递领域。亲水抗癌药物阿霉素DOX·HCl能被成功地包封进囊泡的亲水内腔,载药量和载药效率分别为10.3%和30%。细胞膜仿生囊泡包载药物后能显著降低自由药物的毒性。荧光显微镜表明,载药囊泡同时能够有效地将药物传送到肝癌细胞内。
Polymersomes, self-assembled vesicles of amphiphilic copolymers, usually possess an aqueous interior separated from the outside by the hydrophobic membrane with both external and internal surfaces formed by hydrophilic shells. In recent years, this unique morphology has attracted considerable attention due to their potential applications in biomedicine as drug and gene delivery carriers, artificial cells and bioreactors. However, the utilization of the polymersome as carriers for various therapeutic agents may be the most promising. In this paper, we synthetized diblock copolymers based on phosphorylcholine molecules and studied their self-assembly behavior to construct cell membrane mimetic polymersomes. The potential application of such biocompatible polymersomes as durg carriers was also explored. The main work in this paper foucses on the construction and the formation mechanism of cell-membrane mimetic polymersomes, and the degradation-induced controllable release:
(1) The poly(D,L-lactide)-block-poly(2-methacryloyloxyethyl phosphorylcholine)(PLA-b-PMPC) was specially designed to develop biomimetic giant polymersomes and nano-sized polymersomes via a simple spontaneous assemble in aqueous solution. The weight fraction of the hydrophilic PMPC block (fPC) was proved to play an important role in the size and morphology control of the self-assembled aggregates. The large polymersomes with controlled micro-meter size and biomimetic PMPC corona have great potential as artificial cell models. The nano-sized polymersomes can be used as drug carriers for cancer therapy.
(2) For polymersomes to achieve their potential as effective delivery vehicles, they must efficiently encapsulate therapeutic agents into either the aqueous interior or the hydrophobic membrane. Cell membrane-mimetic polymersomes were prepared from amphiphilic PLA-b-PMPC diblock copolymers and were used as encapsulation devices for water-soluble molecules. Thioalkylated zwitterionic phosphorylcholine protected quantum dots (PC@QDs) were chosen as hydrophilic model substrates and successfully encapsulated into the aqueous polymersome interior, as evidenced by transmission electron microscopy (TEM) and flow cytometry. In addition, we also found a fraction of the PC@QDs was bounded to both the external and internal surfaces of the polymersome. This interesting immobilization might be due to the ion-pair interactions between the phosphorylcholine groups on the PC@QDs and polymersomes. The experimental encapsulation results support amechanism of PLA-b-PMPC polymersome formation, in which PLA-b-PMPC copolymer chains first form spherical micelles, then worm-like micelles, and finally disk-like micelles which close up to form polymersomes.
(3) Nano-sized biocompatible and biodegradable polymersomes were prepared based on PLA-b-PMPC diblock copolymers and applied for the release anti-cancer drugs. Hydrophobic doxorubicin (DOX) and hydrophilic doxorubicin hydrochloride (DOX·HCl) were successfully loaded into the polymersome membrane and polymersome interior, respectively. The in vitro release studies demonstrated that the release of DOX and DOX·HCl from polymersomes was highly pH-dependent, i.e. significantly faster drug release at mildly acidic pH of5.0compared to physiological pH7.4. Furthermore, DOX·HCl-loaded polymersomes exhibited faster drug release than DOX-loaded polymersomes under the same pH conditions. The highly pH-depended release behavior was attributed to the hydrolysis of PLA-b-PMPC, which would result in morphological transformation from polymersome to micelle with a triggered release of the encapsulated drugs. The drug-loaded polymersomes were shown to rapidly enter HepG2cells, localize in their endosome/lysosomes with acidic pH environment and display enhanced intracellular release of the drugs into the cytosol. These biocompatible and acid pH-sensitive polymersomes might have great potential for cancer therapy.
(4) PEO and PMPC are biocompatible polymers that have delivered clinically proven benefits in various biomedical applications. Biocompatible polymer polymersomes were prepared on basis of the inclusion complexation between α-cyclodextrins (α-CDs) and double-hydrophilic PEO-b-PMPC in aqueous media without using organic solvent. The supramolecular structure of the nano-sized vesicles was demonstrated by transmission electron microscopy (TEM), atomic force microscopy (AFM) and dynamic light scattering (DLS). The biocompatibility of PEO-b-PMPC block copolymers and PEO-b-PMPC/a-CDs vesicles were studied by cell viability test, and the results revealed that both of them showed excellent cytocompatibility. Hydrophilic doxorubicin (DOX·HCl) was successfully loaded into the vesicle with loading content of10.3%and loading efficiency of30%. The DOX·HCl loaded vesicles showed lower cytotoxicity than free drugs, and could efficiently deliver and release the drug into HepG2cells as confirmed by fluorescence microscope (FM). With these properties, the polymer vesicles are attractive as drug carriers for pharmaceutical applications.
引文
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