仿细胞膜结构聚合物交联纳米胶束的构建及其应用研究
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摘要
近些年来,两亲性聚合物在选择性溶剂中自组装形成的纳米胶束作为药物传输载体的研究引起了人们的广泛关注。随着这方面研究的进一步深入,人们发现这种在特殊的物理相互作用驱动下形成的自组装聚集体仍存在不稳定的问题,会随着外界环境的变化而发生解缔合。另一方面,一些表面疏水或带有电荷的载药纳米粒子进入体循环后,会很快被体内单核巨噬细胞吞噬系统识别并吞噬,进而被清理出血液循环系统,使药物不能到达病灶部位,大大降低了药物的治疗效果。因此设计稳定性高、且生物相容性良好,对单核巨噬细胞吞噬系统具有隐形效果的长循环纳米药物载体就显得尤为重要。
本文从细胞膜仿生角度出发,以带有磷酰胆碱基团的可聚合单体2-甲基丙烯酰氧乙基磷酰胆碱(MPC)作为亲水性单体,甲基丙烯酸十八烷基酯(SMA)作为疏水性单体,通过γ-甲基丙烯酰氧丙基三甲氧基硅(TSMA)单体引入可交联基团,采用自由基聚合的方法制备一系列单体比例不同的PC基随机共聚物,对各系列聚合物在水中的自组装胶束化、胶束结构的交联固定、所得聚合物胶束对疏水性药物的负载及释药性能进行研究。主要工作包括以下几个方面：
(1)参考文献方法合成重要的仿细胞膜结构可聚合单体MPC,通过传统的自由基聚合方法,采用“饥饿法”加料,合成一系列亲／疏水单体比例及可交联基团含量不同的PC基二元及三元随机聚合物,1H-NMR测试结果表明所得聚合物的组成与单体投料比较为接近。
(2)根据聚合物在水中溶解性能的不同,选择适当方法制备聚合物胶束溶液。芘荧光探针法测得各系列聚合物的临界胶束浓度(CMC)数量级均为10-6 g/mL,远小于小分子表面活性剂的CMC(一般在10-3～104g／mL),且聚合物中疏水性聚合单元含量越多,其CMC越小。含有可交联基团的聚合物胶束溶液在碱性条件下催化交联后,可以使聚合物的CMC减小,且可交联基团含量越高,聚合物CMC降低的程度越大。扫描电镜测试结果表明,此类两亲性PC基随机共聚物在水中可以形成50～300 nm的球形胶束,且交联后的聚合物胶束密度增大,形貌规整,尺寸分布更为均一。
(3)以抗癌药物阿霉素为疏水性模型药物,通过水包油乳化法制备了载药聚合物胶束溶液,碱性条件下催化三甲氧基硅基团水解缩合,得到负载了阿霉素的交联聚合物胶束。通过紫外分光光度法测定了胶束的载药量和包封率。体外药物释放实验结果表明：与游离阿霉素相比,PC基随机共聚物在水中自组装形成的胶束体系对药物具有明显的缓释效果。另外,通过调节聚合物的组成、药物初始加入量以及胶束的交联程度,可以进一步优化聚合物胶束的载药性能以及体外药物释放速率。这种聚合物胶束可望作为具有广阔应用前景的高稳定性、长循环纳米药物缓释体系。
Recently, amphiphilic polymeric micelles as potential nanometer-sized drug delivery vehicles for enhanced therapeutic efficacy and reduced systemic toxicity have aroused extensive attention. However, the assembled architecture is formed under the driven of certain physical interaction, but no covalent linking. A fundamental limitation facting their intravenous application is the dissociation of core-shell micellar structures in physiological environment, especially upon highly dilution in the bloodstream. On the other hand, most of the hydrophobic or charged materials are rapidly cleared from systemic circulation by the mononuclear phagocyte system (MPS), which is thought to be preceded by the absorption of serum proteinaceous molecules to the surface of polymeric nanoparticles. Therefore, the design of prolonged circulating nanomicellar drug carriers with enhanced stability and good biocompatibility is the current crucial objective.
In this thesis, by mimicking the chemical functionality as well as the molecular structure of phospholipids in the plasma membrane, a series of random phospholipid copolymers PMS used as a control and crosslinkable terpolymers PMST comprising 2-methacryloyloxyethyl phosphorylcholine (MPC) as a hydrophilic monomer, stearyl methacrylate (SMA) as a hydrophobic part, and trimethoxysilylpropyl methacrylate (TSMA) as a crosslinker were specially designed as drug delivery systems. The micellization behavior of these amphiphilic polymers in aqueous medium and the condition of intramicellar crosslinking were studied. The self-associative property of stearyl group in the polymers ensure that drugs with a hydrophobic character can be easily incorporated into the inner-core by a non-covalent bonding through hydrophobic interactions. The research was mainly concerned with the following aspects.
(1) Firstly, the most important polymerizable monomer MPC, having the biomimicing structure, was prepared according to the traditional synthetic route. The structure and purity was confirmed by 1H-NMR. Then a series of crosslinkable terpolymers PMST with different compositions and reference copolymers PMS were synthesized using a free radical polymerization through "monomer-starved" approach. The formulation of resulting materials were characterised by 1H-NMR in 1:1 CDCl3:CD3OD, which gives the best resolution of groups within different moieties, and proved that the average polymer compositions approximately correspond to their feed ratios.
(2) Polymeric micelles were prepared using proper methods according to the solubility of different polymers. Fluorescence technique was used to determine the critical micelle concentration (CMC) using pyrene as probe. The results showed that the CMC value of those crosslinkable phosphllipid polymers were at the level of 10-6g/mL and decreased remarkably after intramicellar crosslinking. Scanning electron microscope (SEM) characterization suggested that these amphiphilic random polymers formed 50-300 nm regularized spherical aggregates in water and the crosslinked micellar shape was more uniform and exhibited a narrow size distribution. Finally, the crosslinked micelle stability against dilution in water and the shell permeability were studied. The results demonstrated that covalent crosslinking technique is an effective way to enhance the stability of the corresponding self-assembled structure and improve temporal control for drug delivery.
(3) Anti-cancer drug adriamycin (ADR) was chosen as a hydrophobic drug model to be incorporated into the inner-core of micelles by oil-in-water method. Ultraviolet and visible spectrophotometry (UV-Vis) analysis suggested that high ADR loading capacities are obtained. In vitro drug release evaluation was performed using a dialysis method and proved that the drug-loaded crosslinked nano-micelles present a sustained and remarkably slower release behavior without any burst effect while free ADR release very quickly under the same experimental conditions. Moreover, the release rate decreased with the increase of SMA molar ratio in polymer and the amount of the drug entrapped. These experimental results suggested that the crosslinked micelles prepared from PMST random terpolymers with a biomimetic and anti-biofouling shell could be a promising candidate for prolonged circulating drug delivery carriers, especially for intravenous administration.
本文从细胞膜仿生角度出发,以带有磷酰胆碱基团的可聚合单体2-甲基丙烯酰氧乙基磷酰胆碱(MPC)作为亲水性单体,甲基丙烯酸十八烷基酯(SMA)作为疏水性单体,通过γ-甲基丙烯酰氧丙基三甲氧基硅(TSMA)单体引入可交联基团,采用自由基聚合的方法制备一系列单体比例不同的PC基随机共聚物,对各系列聚合物在水中的自组装胶束化、胶束结构的交联固定、所得聚合物胶束对疏水性药物的负载及释药性能进行研究。主要工作包括以下几个方面：
(1)参考文献方法合成重要的仿细胞膜结构可聚合单体MPC,通过传统的自由基聚合方法,采用“饥饿法”加料,合成一系列亲／疏水单体比例及可交联基团含量不同的PC基二元及三元随机聚合物,1H-NMR测试结果表明所得聚合物的组成与单体投料比较为接近。
(2)根据聚合物在水中溶解性能的不同,选择适当方法制备聚合物胶束溶液。芘荧光探针法测得各系列聚合物的临界胶束浓度(CMC)数量级均为10-6 g/mL,远小于小分子表面活性剂的CMC(一般在10-3～104g／mL),且聚合物中疏水性聚合单元含量越多,其CMC越小。含有可交联基团的聚合物胶束溶液在碱性条件下催化交联后,可以使聚合物的CMC减小,且可交联基团含量越高,聚合物CMC降低的程度越大。扫描电镜测试结果表明,此类两亲性PC基随机共聚物在水中可以形成50～300 nm的球形胶束,且交联后的聚合物胶束密度增大,形貌规整,尺寸分布更为均一。
(3)以抗癌药物阿霉素为疏水性模型药物,通过水包油乳化法制备了载药聚合物胶束溶液,碱性条件下催化三甲氧基硅基团水解缩合,得到负载了阿霉素的交联聚合物胶束。通过紫外分光光度法测定了胶束的载药量和包封率。体外药物释放实验结果表明：与游离阿霉素相比,PC基随机共聚物在水中自组装形成的胶束体系对药物具有明显的缓释效果。另外,通过调节聚合物的组成、药物初始加入量以及胶束的交联程度,可以进一步优化聚合物胶束的载药性能以及体外药物释放速率。这种聚合物胶束可望作为具有广阔应用前景的高稳定性、长循环纳米药物缓释体系。
Recently, amphiphilic polymeric micelles as potential nanometer-sized drug delivery vehicles for enhanced therapeutic efficacy and reduced systemic toxicity have aroused extensive attention. However, the assembled architecture is formed under the driven of certain physical interaction, but no covalent linking. A fundamental limitation facting their intravenous application is the dissociation of core-shell micellar structures in physiological environment, especially upon highly dilution in the bloodstream. On the other hand, most of the hydrophobic or charged materials are rapidly cleared from systemic circulation by the mononuclear phagocyte system (MPS), which is thought to be preceded by the absorption of serum proteinaceous molecules to the surface of polymeric nanoparticles. Therefore, the design of prolonged circulating nanomicellar drug carriers with enhanced stability and good biocompatibility is the current crucial objective.
In this thesis, by mimicking the chemical functionality as well as the molecular structure of phospholipids in the plasma membrane, a series of random phospholipid copolymers PMS used as a control and crosslinkable terpolymers PMST comprising 2-methacryloyloxyethyl phosphorylcholine (MPC) as a hydrophilic monomer, stearyl methacrylate (SMA) as a hydrophobic part, and trimethoxysilylpropyl methacrylate (TSMA) as a crosslinker were specially designed as drug delivery systems. The micellization behavior of these amphiphilic polymers in aqueous medium and the condition of intramicellar crosslinking were studied. The self-associative property of stearyl group in the polymers ensure that drugs with a hydrophobic character can be easily incorporated into the inner-core by a non-covalent bonding through hydrophobic interactions. The research was mainly concerned with the following aspects.
(1) Firstly, the most important polymerizable monomer MPC, having the biomimicing structure, was prepared according to the traditional synthetic route. The structure and purity was confirmed by 1H-NMR. Then a series of crosslinkable terpolymers PMST with different compositions and reference copolymers PMS were synthesized using a free radical polymerization through "monomer-starved" approach. The formulation of resulting materials were characterised by 1H-NMR in 1:1 CDCl3:CD3OD, which gives the best resolution of groups within different moieties, and proved that the average polymer compositions approximately correspond to their feed ratios.
(2) Polymeric micelles were prepared using proper methods according to the solubility of different polymers. Fluorescence technique was used to determine the critical micelle concentration (CMC) using pyrene as probe. The results showed that the CMC value of those crosslinkable phosphllipid polymers were at the level of 10-6g/mL and decreased remarkably after intramicellar crosslinking. Scanning electron microscope (SEM) characterization suggested that these amphiphilic random polymers formed 50-300 nm regularized spherical aggregates in water and the crosslinked micellar shape was more uniform and exhibited a narrow size distribution. Finally, the crosslinked micelle stability against dilution in water and the shell permeability were studied. The results demonstrated that covalent crosslinking technique is an effective way to enhance the stability of the corresponding self-assembled structure and improve temporal control for drug delivery.
(3) Anti-cancer drug adriamycin (ADR) was chosen as a hydrophobic drug model to be incorporated into the inner-core of micelles by oil-in-water method. Ultraviolet and visible spectrophotometry (UV-Vis) analysis suggested that high ADR loading capacities are obtained. In vitro drug release evaluation was performed using a dialysis method and proved that the drug-loaded crosslinked nano-micelles present a sustained and remarkably slower release behavior without any burst effect while free ADR release very quickly under the same experimental conditions. Moreover, the release rate decreased with the increase of SMA molar ratio in polymer and the amount of the drug entrapped. These experimental results suggested that the crosslinked micelles prepared from PMST random terpolymers with a biomimetic and anti-biofouling shell could be a promising candidate for prolonged circulating drug delivery carriers, especially for intravenous administration.
引文
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