新型两亲性聚合物纳米材料的制备及其在药物输送中的应用
发布时间：2018-11-06 16:32
【摘要】：高分子纳米材料具有独特的物理和化学性质,使其在不同领域中得到广泛的应用。与此同时具有各种功能的高分子纳米材料在生物医药领域的发展也十分迅速。作为药物载体的两亲性嵌段聚合物中,能用作疏水性链段的聚合物种类单一,因此寻找新的疏水性链段迫在眉睫。本文主要通过开环聚合(ROP)、可逆加成-断裂链转移聚合(RAFT)和自由基聚合等聚合手段,设计并合成一系列新型嵌段共聚物和聚合物荧光纳米颗粒并应用于药物缓释和细胞成像中。具体内容如下:1、为了提高疏水性抗癌药物阿霉素(DOX)在肿瘤治疗中药物的利用率,我们以聚十三碳二元酸环乙撑酯(Poly(ethylene brassylate),PEB)作为疏水性链段制备了聚乙二醇单甲醚-b-聚十三碳二元酸环乙撑酯(PEG-b-PEB)两亲性嵌段聚合物,并用作抗癌药物DOX的载体。我们通过调节反应时间以及单体和引发剂的比例制备出含不同PEB分子量的嵌段聚合物。采用核磁共振波谱仪(1H NMR)和凝胶渗透色谱仪(GPC)对嵌段聚合物的化学结构进行了确认,同时对分子量大小及分布进行了测试。并采用透射电子显微镜(TEM)和动态光散射仪(DLS)对PEG-b-PEB的自组装纳米胶束的形貌和粒径进行表征。最后我们以DOX为药物模型考察了不同分子量PEG-b-PEB胶束的药物缓释性能。2、为了克服传统的线型两亲性嵌段聚合物载药胶束在体内循环过程中稳定性不佳的问题,我们通过开环聚合和可逆加成-断裂链转移聚合的方法制备出结构新颖的四臂星型嵌段聚合物。合成过程中,我们首先以季戊四醇为引发剂开环聚合十三碳二元酸环乙撑酯得到四臂星型均聚物(S-PEB),然后通过简单的酯化反应在S-PEB链末端修饰链转移剂(CTA),最后通过RAFT聚合的方法合成四臂嵌段聚合物聚十三碳二元酸环乙撑酯-b-聚乙二醇甲基丙烯酸甲酯(S-PEB-b-P(PEGM A))。在水溶液中,S-PEB-b-P(PEGMA)能自组装形成以PEB为核以P(PEGMA)为壳的核-壳纳米胶束。我们利用TEM和DLS对S-PEB-b-P(PEGMA)自组装胶束的形貌和粒径分布进行观察研究。体外药物缓释实验结果表明,S-PEB-b-P(PEGMA)自组装胶束具有较高的载药量和良好的缓释效果。3、为了改善疏水性碳量子点(Carbon Dots,CDs)在水溶液中的分散性和荧光性能,我们通过在疏水性碳点表面修饰上甲基丙烯酰氯,制备出可聚合的碳量子点。随后将可聚合的碳量子点和N-异丙基丙烯酰胺单体(NIPAM)共聚得到聚N-异丙基丙烯酰胺(PNIPAM)接枝CDs荧光聚合物(CDs-g-PNIPAM)。相比于单纯的CDs,CDs-g-PNIPAM在水溶液中具有良好的溶解性以及优异的温度响应性。MTT实验结果表明,CDs-g-PNIPAM与人体永生化表皮细胞(HaCaT细胞)共培养时,即使CDs-g-PNIPAM浓度达到2000μg mL-1时,细胞相对存活率仍然能维持在85%以上。体外细胞成像实验表明,CDs-g-PNIPAM在细胞内具有很好的荧光稳定性,非常适用于细胞长效成像。
[Abstract]:Polymer nanomaterials are widely used in different fields because of their unique physical and chemical properties. At the same time, polymer nanomaterials with various functions are developing rapidly in the field of biomedicine. Among the amphiphilic block polymers used as drug carriers, the kinds of polymers that can be used as hydrophobic segments are single, so it is urgent to find new hydrophobic segments. In this paper, the reversible addition-break chain transfer polymerization (RAFT) and free radical polymerization of (ROP), were carried out. A series of novel block copolymers and polymer fluorescent nanoparticles were designed and synthesized for drug delivery and cell imaging. The specific contents are as follows: 1. In order to improve the utilization rate of adriamycin (DOX), a hydrophobic anticancer drug, we used poly (tridecyl dicarboxylic acid) cycloethylenes (Poly (ethylene brassylate),) in tumor therapy. Polyethylene glycol monomethyl ether (PEG-b-PEB) amphiphilic block polymer (PEG-b-PEB) was prepared by using PEB as hydrophobic segment and used as a carrier of anticancer drug DOX. Block polymers with different molecular weights of PEB were prepared by adjusting the reaction time and the ratio of monomer to initiator. The chemical structure of the block polymer was confirmed by 1H NMR and (GPC). The molecular weight and distribution of the block polymer were also tested. The morphology and particle size of self-assembled nano-micelles of PEG-b-PEB were characterized by transmission electron microscope (TEM) (TEM) and dynamic light scattering (DLS). Finally, we used DOX as a drug model to investigate the drug release properties of PEG-b-PEB micelles with different molecular weights. 2. In order to overcome the problem of poor stability of traditional linear amphiphilic block polymer micelles in vivo circulation. Novel four-arm star block polymers were prepared by ring-opening polymerization and reversible addition-break chain transfer polymerization. In the synthesis process, pentaerythritol was used as initiator to polymerize cycloethylene-tridecarbamate to obtain four-arm star homopolymer (S-PEB), and then (CTA), was modified at the end of S-PEB chain by simple esterification reaction. Finally, the four-arm block polymer poly (cycloethylene-tridecanoic acid) -b- poly (ethylene glycol methacrylate) (S-PEB-b-P (PEGM A).) was synthesized by RAFT polymerization. In aqueous solution, S-PEB-b-P (PEGMA) can self-assemble into core-shell nano-micelles with PEB as core and P (PEGMA) as shell. The morphology and particle size distribution of S-PEB-b-P (PEGMA) self-assembled micelles were observed by TEM and DLS. In vitro drug release experiments showed that S-PEB-b-P (PEGMA) self-assembled micelles had high drug loading and good sustained release effect. 3. In order to improve hydrophobic carbon quantum dot (Carbon Dots, The dispersibility and fluorescence properties of CDs) in aqueous solution. We prepared polymerizable carbon quantum dots by modifying methacryloyl chloride on the surface of hydrophobic carbon spots. The polymerizable carbon quantum dots (QDs) were then copolymerized with N-isopropylacrylamide monomer (NIPAM) to obtain poly (N-isopropylacrylamide) (PNIPAM) grafted CDs fluorescent polymer (CDs-g-PNIPAM). Compared with pure CDs,CDs-g-PNIPAM, it has good solubility and excellent temperature response in aqueous solution. MTT results show that CDs-g-PNIPAM is co-cultured with human immortalized epidermal cells (HaCaT cells). Even when the concentration of CDs-g-PNIPAM reached 2000 渭 g mL-1, the relative survival rate of the cells remained above 85%. In vitro cell imaging experiments show that CDs-g-PNIPAM has good fluorescence stability in cells and is very suitable for long-term imaging of cells.
【学位授予单位】：西南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O631;TQ460.1
本文编号：2314839
[Abstract]:Polymer nanomaterials are widely used in different fields because of their unique physical and chemical properties. At the same time, polymer nanomaterials with various functions are developing rapidly in the field of biomedicine. Among the amphiphilic block polymers used as drug carriers, the kinds of polymers that can be used as hydrophobic segments are single, so it is urgent to find new hydrophobic segments. In this paper, the reversible addition-break chain transfer polymerization (RAFT) and free radical polymerization of (ROP), were carried out. A series of novel block copolymers and polymer fluorescent nanoparticles were designed and synthesized for drug delivery and cell imaging. The specific contents are as follows: 1. In order to improve the utilization rate of adriamycin (DOX), a hydrophobic anticancer drug, we used poly (tridecyl dicarboxylic acid) cycloethylenes (Poly (ethylene brassylate),) in tumor therapy. Polyethylene glycol monomethyl ether (PEG-b-PEB) amphiphilic block polymer (PEG-b-PEB) was prepared by using PEB as hydrophobic segment and used as a carrier of anticancer drug DOX. Block polymers with different molecular weights of PEB were prepared by adjusting the reaction time and the ratio of monomer to initiator. The chemical structure of the block polymer was confirmed by 1H NMR and (GPC). The molecular weight and distribution of the block polymer were also tested. The morphology and particle size of self-assembled nano-micelles of PEG-b-PEB were characterized by transmission electron microscope (TEM) (TEM) and dynamic light scattering (DLS). Finally, we used DOX as a drug model to investigate the drug release properties of PEG-b-PEB micelles with different molecular weights. 2. In order to overcome the problem of poor stability of traditional linear amphiphilic block polymer micelles in vivo circulation. Novel four-arm star block polymers were prepared by ring-opening polymerization and reversible addition-break chain transfer polymerization. In the synthesis process, pentaerythritol was used as initiator to polymerize cycloethylene-tridecarbamate to obtain four-arm star homopolymer (S-PEB), and then (CTA), was modified at the end of S-PEB chain by simple esterification reaction. Finally, the four-arm block polymer poly (cycloethylene-tridecanoic acid) -b- poly (ethylene glycol methacrylate) (S-PEB-b-P (PEGM A).) was synthesized by RAFT polymerization. In aqueous solution, S-PEB-b-P (PEGMA) can self-assemble into core-shell nano-micelles with PEB as core and P (PEGMA) as shell. The morphology and particle size distribution of S-PEB-b-P (PEGMA) self-assembled micelles were observed by TEM and DLS. In vitro drug release experiments showed that S-PEB-b-P (PEGMA) self-assembled micelles had high drug loading and good sustained release effect. 3. In order to improve hydrophobic carbon quantum dot (Carbon Dots, The dispersibility and fluorescence properties of CDs) in aqueous solution. We prepared polymerizable carbon quantum dots by modifying methacryloyl chloride on the surface of hydrophobic carbon spots. The polymerizable carbon quantum dots (QDs) were then copolymerized with N-isopropylacrylamide monomer (NIPAM) to obtain poly (N-isopropylacrylamide) (PNIPAM) grafted CDs fluorescent polymer (CDs-g-PNIPAM). Compared with pure CDs,CDs-g-PNIPAM, it has good solubility and excellent temperature response in aqueous solution. MTT results show that CDs-g-PNIPAM is co-cultured with human immortalized epidermal cells (HaCaT cells). Even when the concentration of CDs-g-PNIPAM reached 2000 渭 g mL-1, the relative survival rate of the cells remained above 85%. In vitro cell imaging experiments show that CDs-g-PNIPAM has good fluorescence stability in cells and is very suitable for long-term imaging of cells.
【学位授予单位】：西南大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O631;TQ460.1
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