新型超枝化嵌段共聚物在药物控释体系中的研究
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摘要
纳米粒子在作为药物载体方面的应用是目前的科学前沿,它们可以通过吸附和包埋的方式将活性药物装载到其基质上,对提高药物利用率和保持药物活性起到至关重要的作用。两亲性嵌段共聚物纳米粒子作为给药载体,在药物控释、靶向器官和组织、运送蛋白质和基因药物等方面作用巨大,引起了人们的广泛关注。本文合成了超枝化聚缩水甘油醚(HPG)-聚乳酸(PLA)两亲性共聚物,制备了纳米粒子,评价了其物理化学性质。材料合成方法简单,纳米粒子的载药量高、释药速率可控性强,有望成为新型的给药系统。
一、共聚物的合成
合成了一系列生物可降解和相容性好的超枝化聚缩水甘油醚-聚乳酸两亲性嵌段共聚物(HPG-PLA)。材料制备条件温和；改变反应过程中HPG和PLA的投料比,可以控制共聚物的结构。
二、共聚物纳米粒子的物化性质
1.共聚物纳米粒子的载药量
共聚物纳米粒子对小分子疏水性药物(槲皮素为药物模型)载药量在优化的条件下可达26.5%。药物不仅能够和疏水的PLA片段通过分子间相互作用相结合,而且能够进入支化的HPG当中,所以载药量较高。
共聚物纳米粒子对大分子蛋白质药物(BSA为药物模型)载药量在优化的条件下可达23.0%。蛋白不仅能够和疏水的PLA片段通过亲疏水相互作用形成复合体,而且能够通过静电相互作用和HPG相连接,同时蛋白表面的氨基酸残基可以和支化的HPG相互作用,因此载药量较高。
2.载药纳米粒子的释放行为
载大分子类蛋白和小分子疏水性药物的纳米粒子,释放行为都分为两个阶段。起初的突释阶段,由纳米粒子表面附近的药物释放导致；随后的缓释阶段,由纳米粒子内部包埋的药物释放导致。蛋白类物质总释放时间达到4天,小分子药物总释放时间可达10天；共聚物纳米粒子可作为药物的缓释载体。
随着共聚物结构、分子量、释放介质pH值和纳米粒子载药量的不同,药物释放行为的差异性较大；通过改变或调节上述因素,可以精确调控载药系统的释放行为,从而开发出能够满足特定释放需要的药物载体。
为了认识载药纳米粒子的释放机制,本文以载蛋白类纳米粒子为例,用多种数学模型对其释放的实验数据进行了拟合。结果显示,蛋白的扩散和组成纳米粒子共聚物的松弛共同决定着载药纳米粒子的释放行为；而共聚物的降解并未对释放产生明显的影响。这为设计出能够满足特定释放需要的药物载体提供了理论基础。
Nanoparticle research is currently an area of intense scientific research, due to a wide variety of potential applications. As a drug carrier, it can both entrap guest molecules in and adsorb them on the surface of the matrix, which is important for increasing drug efficiency and protecting its bioactivity. Amphiphilic biodegradable block copolymer nanoparticles play an important role in controlled release of drugs, targeting a tissue or organ, transporting biomolecules and generic drug as drug carriers. They have attracted increasing attention. In the present study, a novel poly lactic acid (PLA) functionalized hyperbranched polyglycerol (HPG) had been prepared and physicochemically characterized with the prospect of its application as a drug delivery system. Specifically, functional polymers derived from HPG were prepared that bear at the external surface PLA chains. Nanoparticles fabricated from the copolymer had nontoxic, biocompatible and biodegradable characteristics and high encapsulation capacity. Therefore, they have a promising potential as a novel drug delivery system.
Ⅰ, Synthesis of copolymers
The amphiphilic copolymers were synthesized by a typical coupling reaction of PLA chains onto modified HPG in the existence of coupling agents. The number of PLA chains grafted onto HPG could be controlled by changing the feeding ratio of PLA to HPG. A series of copolymers were synthesized by using HPG and PLA with different molecular weight. The experimental results suggested that the biodegradable products have good biocompatibility.
Ⅱ, Physicochemical Characterization of the copolymer nanoparticles
1. The loading capacity of the copolymer nanoparticles
The loading capacity of the copolymer nanoparticles to small hydrophobic molecules (quercetin as model drug) could reach to 26.5% under optimized conditions. Quercetin dispersed both into HPG and formed an amorphous complex with intermolecular interaction occurring within the matrices, which were favorable for increasing loading capacity.
The loading capacity of the copolymer nanoparticles to biomacromolecules (BSA as model drug) could reach to 23.0% under optimized conditions. BSA dispersed both on the surface of nanoparticles by electrostatic interaction and formed a complex within the matrices by hydrophilic and hydrophobic interactions, which were favorable for increasing loading capacity.
2. In vitro drug release
In all curves (both BSA and quercetin) a burst effect was observed followed by a slowly continuous release phase. The initial release burst corresponded to the diffusion of drugs located on the nanoparticle surfaces. The slow release profile corresponded to the release of drugs entrapped in the nanoparticles. The release time could reach 4 days for BSA and 10 days for quercetin, respectively. The copolymer nanoparticles could be used as sustained-release carriers.
The release profiles could be influenced significantly by many factors (polymer composition, molecular weight, pH and drug loading capacity). The relevant relationship that existed between the characteristics of nanoparticles and the release behavior could be exploited to develop unique drug delivery system with exclusively defined release properties.
In order to understand the release mechanism of nanoparticles, BSA release profiles from nanoparticles were investigated. Based on the experimental results, mathematical models were proposed to predict protein release mechanism from nanoparticle populations. The results obtained during experimental and mathematical analysis showed that two mechanisms of BSA release, namely protein diffusion and macromolecular relaxation, combined to control the release process. The degradation rate was quite low and the protein release may not be an erosion control process. The relevant relationship that existed between the characteristics of nanoparticles and the release behavior could be exploited to develop unique protein delivery system with exclusively defined release properties.
一、共聚物的合成
合成了一系列生物可降解和相容性好的超枝化聚缩水甘油醚-聚乳酸两亲性嵌段共聚物(HPG-PLA)。材料制备条件温和；改变反应过程中HPG和PLA的投料比,可以控制共聚物的结构。
二、共聚物纳米粒子的物化性质
1.共聚物纳米粒子的载药量
共聚物纳米粒子对小分子疏水性药物(槲皮素为药物模型)载药量在优化的条件下可达26.5%。药物不仅能够和疏水的PLA片段通过分子间相互作用相结合,而且能够进入支化的HPG当中,所以载药量较高。
共聚物纳米粒子对大分子蛋白质药物(BSA为药物模型)载药量在优化的条件下可达23.0%。蛋白不仅能够和疏水的PLA片段通过亲疏水相互作用形成复合体,而且能够通过静电相互作用和HPG相连接,同时蛋白表面的氨基酸残基可以和支化的HPG相互作用,因此载药量较高。
2.载药纳米粒子的释放行为
载大分子类蛋白和小分子疏水性药物的纳米粒子,释放行为都分为两个阶段。起初的突释阶段,由纳米粒子表面附近的药物释放导致；随后的缓释阶段,由纳米粒子内部包埋的药物释放导致。蛋白类物质总释放时间达到4天,小分子药物总释放时间可达10天；共聚物纳米粒子可作为药物的缓释载体。
随着共聚物结构、分子量、释放介质pH值和纳米粒子载药量的不同,药物释放行为的差异性较大；通过改变或调节上述因素,可以精确调控载药系统的释放行为,从而开发出能够满足特定释放需要的药物载体。
为了认识载药纳米粒子的释放机制,本文以载蛋白类纳米粒子为例,用多种数学模型对其释放的实验数据进行了拟合。结果显示,蛋白的扩散和组成纳米粒子共聚物的松弛共同决定着载药纳米粒子的释放行为；而共聚物的降解并未对释放产生明显的影响。这为设计出能够满足特定释放需要的药物载体提供了理论基础。
Nanoparticle research is currently an area of intense scientific research, due to a wide variety of potential applications. As a drug carrier, it can both entrap guest molecules in and adsorb them on the surface of the matrix, which is important for increasing drug efficiency and protecting its bioactivity. Amphiphilic biodegradable block copolymer nanoparticles play an important role in controlled release of drugs, targeting a tissue or organ, transporting biomolecules and generic drug as drug carriers. They have attracted increasing attention. In the present study, a novel poly lactic acid (PLA) functionalized hyperbranched polyglycerol (HPG) had been prepared and physicochemically characterized with the prospect of its application as a drug delivery system. Specifically, functional polymers derived from HPG were prepared that bear at the external surface PLA chains. Nanoparticles fabricated from the copolymer had nontoxic, biocompatible and biodegradable characteristics and high encapsulation capacity. Therefore, they have a promising potential as a novel drug delivery system.
Ⅰ, Synthesis of copolymers
The amphiphilic copolymers were synthesized by a typical coupling reaction of PLA chains onto modified HPG in the existence of coupling agents. The number of PLA chains grafted onto HPG could be controlled by changing the feeding ratio of PLA to HPG. A series of copolymers were synthesized by using HPG and PLA with different molecular weight. The experimental results suggested that the biodegradable products have good biocompatibility.
Ⅱ, Physicochemical Characterization of the copolymer nanoparticles
1. The loading capacity of the copolymer nanoparticles
The loading capacity of the copolymer nanoparticles to small hydrophobic molecules (quercetin as model drug) could reach to 26.5% under optimized conditions. Quercetin dispersed both into HPG and formed an amorphous complex with intermolecular interaction occurring within the matrices, which were favorable for increasing loading capacity.
The loading capacity of the copolymer nanoparticles to biomacromolecules (BSA as model drug) could reach to 23.0% under optimized conditions. BSA dispersed both on the surface of nanoparticles by electrostatic interaction and formed a complex within the matrices by hydrophilic and hydrophobic interactions, which were favorable for increasing loading capacity.
2. In vitro drug release
In all curves (both BSA and quercetin) a burst effect was observed followed by a slowly continuous release phase. The initial release burst corresponded to the diffusion of drugs located on the nanoparticle surfaces. The slow release profile corresponded to the release of drugs entrapped in the nanoparticles. The release time could reach 4 days for BSA and 10 days for quercetin, respectively. The copolymer nanoparticles could be used as sustained-release carriers.
The release profiles could be influenced significantly by many factors (polymer composition, molecular weight, pH and drug loading capacity). The relevant relationship that existed between the characteristics of nanoparticles and the release behavior could be exploited to develop unique drug delivery system with exclusively defined release properties.
In order to understand the release mechanism of nanoparticles, BSA release profiles from nanoparticles were investigated. Based on the experimental results, mathematical models were proposed to predict protein release mechanism from nanoparticle populations. The results obtained during experimental and mathematical analysis showed that two mechanisms of BSA release, namely protein diffusion and macromolecular relaxation, combined to control the release process. The degradation rate was quite low and the protein release may not be an erosion control process. The relevant relationship that existed between the characteristics of nanoparticles and the release behavior could be exploited to develop unique protein delivery system with exclusively defined release properties.
引文
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