烷基壳聚糖纳米微球的制备及其药物负载性能研究
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摘要
壳聚糖作为优良的天然聚阳离子材料，拥有良好的可生物降解、生物相容等性能，已被用于药物控释、靶向、智能给药等多种药物载体的研究，而将壳聚糖烷基化后得到的烷基壳聚糖在水中以烷基为核自动形成纳米范围的聚集体（self-aggregates），并可作为非水溶性药物的水性载体。
在碱性条件下，将壳聚糖与多种卤代烷发生烷基取代的接枝反应，得到烷基化的壳聚糖，并使用元素分析的方法确定了烷基反应的取代度。经红外光谱研究表明，烷基化反应主要发生在壳聚糖分子中的氨基上。对烷基化壳聚糖进行X射线光电子能谱分析表明，随着卤代烷试剂反应活性的增高，发生在壳聚糖羟基上的烷基取代反应增多。
烷基壳聚糖纳米微球水分散液的粒径分布和平均粒径使用动态光散射法测量，而这些纳米微球的形态则采用透射电镜法进行测量。结果表明，烷基壳聚糖纳米微球拥有明显的核/壳结构，其粒径尺寸在20～200nm之间。附载药物之后，微球的内核发生了较明显的变化，并且粒径增大。
以紫杉醇和扑热息痛为模型药物考查了烷基壳聚糖纳米粒子的药物负载性能以及体外释放性能，结果表明这种壳聚糖纳米粒子对非水溶性的紫杉醇有良好的负载作用。随着烷基取代度的增加，有利于其对扑热息痛和紫杉醇的负载能力提高。体外释放研究表明，与水亲合力较高的扑热息痛从烷基壳聚糖纳米微球中释放的速度较快，有明显突释的现象，而不溶于水的紫杉醇的释放则表现出了明显的缓释效果。从总体来看，这种壳聚糖纳米微球对紫杉醇的负载能力超过对扑热息痛的负载能力。
采用多种常用药学体外释放模型对烷基壳聚糖纳米微球负载扑热息痛以及紫杉醇的体外释放进行了拟合，发现Weibull模型能够较好的拟合多种体系下的释放情况，一级动力学模型也能较好的拟合扑热息痛的体外释放情况。而假定药物的溶解速度为药物释放的控制步骤所建立的溶解模型，能够良好的预测扑热息痛的体外释放情况。
Chitosan (CS) is a natural cationic polysaccharide. As a biocompatible and slowly degradable polymer, chitosan has been widely used in drug delivery systems (DDS) especially in drug-controlled release, targeting, and intellectualized delivery system. After modified chemically by alkyl, this kind of alkyl-chitosan consisting of hydrophilic and hydrophobic segments can form nanoparticles with core/shell structure in aqueous media. These nanoparticles have been proposed to use as drug delivery vehicles for poorly water-soluble drugs.
Infrared (IR) spectra of alkyl-chitosan revealed that there was a substitution reaction mainly on the amine groups of CS. X-ray photoelectron spectroscopy (XPS) indicated that the higher reaction activity of alkyl halide, the more alkyl substitution degree on hydroxyl group of chitosan. The sizes of alkyl-chitosan aggregates were measured by Dynamic Light Scattering(DLS). The morphology of alkyl-chitosan nanoparticles (ACNPs) was investigated by Transmission Electron Microscope(TEM). The result showed that the ACNPs appeared spheres with a core/shell structure and a scale of 20 to 200nm in size. After carrying drugs, there are obvious changes in the cores of particles with larger diameters.
By using paracetamol (PCTM) and paclitaxel (taxol(r)) as model drugs, the vitro release rates of drugs from ACNPs in phosphate buffer solution (PBS, pH=7.4) can be delayed with the increase of degree of substitution alkyl and the increase of carbon chain length of alkyl substituting group. The release of PCTM from ACNPs, however, is much fast than paclitaxel in PBS with a burst effect.
Several mathematical models of drug release were used to fit the vitro release of PCTM and taxol from ACNPs. The Weibull model could fit better both PCTM and taxol release profile, and the first order model could fit PCTM release profile better. The dissolution model could fit release profiles of PCTM best than Weibull model and first order model, which was formulated by to assume that the dissolution of PCTM crystals was considered the rate-controlling mechanism of drug release.
在碱性条件下，将壳聚糖与多种卤代烷发生烷基取代的接枝反应，得到烷基化的壳聚糖，并使用元素分析的方法确定了烷基反应的取代度。经红外光谱研究表明，烷基化反应主要发生在壳聚糖分子中的氨基上。对烷基化壳聚糖进行X射线光电子能谱分析表明，随着卤代烷试剂反应活性的增高，发生在壳聚糖羟基上的烷基取代反应增多。
烷基壳聚糖纳米微球水分散液的粒径分布和平均粒径使用动态光散射法测量，而这些纳米微球的形态则采用透射电镜法进行测量。结果表明，烷基壳聚糖纳米微球拥有明显的核/壳结构，其粒径尺寸在20～200nm之间。附载药物之后，微球的内核发生了较明显的变化，并且粒径增大。
以紫杉醇和扑热息痛为模型药物考查了烷基壳聚糖纳米粒子的药物负载性能以及体外释放性能，结果表明这种壳聚糖纳米粒子对非水溶性的紫杉醇有良好的负载作用。随着烷基取代度的增加，有利于其对扑热息痛和紫杉醇的负载能力提高。体外释放研究表明，与水亲合力较高的扑热息痛从烷基壳聚糖纳米微球中释放的速度较快，有明显突释的现象，而不溶于水的紫杉醇的释放则表现出了明显的缓释效果。从总体来看，这种壳聚糖纳米微球对紫杉醇的负载能力超过对扑热息痛的负载能力。
采用多种常用药学体外释放模型对烷基壳聚糖纳米微球负载扑热息痛以及紫杉醇的体外释放进行了拟合，发现Weibull模型能够较好的拟合多种体系下的释放情况，一级动力学模型也能较好的拟合扑热息痛的体外释放情况。而假定药物的溶解速度为药物释放的控制步骤所建立的溶解模型，能够良好的预测扑热息痛的体外释放情况。
Chitosan (CS) is a natural cationic polysaccharide. As a biocompatible and slowly degradable polymer, chitosan has been widely used in drug delivery systems (DDS) especially in drug-controlled release, targeting, and intellectualized delivery system. After modified chemically by alkyl, this kind of alkyl-chitosan consisting of hydrophilic and hydrophobic segments can form nanoparticles with core/shell structure in aqueous media. These nanoparticles have been proposed to use as drug delivery vehicles for poorly water-soluble drugs.
Infrared (IR) spectra of alkyl-chitosan revealed that there was a substitution reaction mainly on the amine groups of CS. X-ray photoelectron spectroscopy (XPS) indicated that the higher reaction activity of alkyl halide, the more alkyl substitution degree on hydroxyl group of chitosan. The sizes of alkyl-chitosan aggregates were measured by Dynamic Light Scattering(DLS). The morphology of alkyl-chitosan nanoparticles (ACNPs) was investigated by Transmission Electron Microscope(TEM). The result showed that the ACNPs appeared spheres with a core/shell structure and a scale of 20 to 200nm in size. After carrying drugs, there are obvious changes in the cores of particles with larger diameters.
By using paracetamol (PCTM) and paclitaxel (taxol(r)) as model drugs, the vitro release rates of drugs from ACNPs in phosphate buffer solution (PBS, pH=7.4) can be delayed with the increase of degree of substitution alkyl and the increase of carbon chain length of alkyl substituting group. The release of PCTM from ACNPs, however, is much fast than paclitaxel in PBS with a burst effect.
Several mathematical models of drug release were used to fit the vitro release of PCTM and taxol from ACNPs. The Weibull model could fit better both PCTM and taxol release profile, and the first order model could fit PCTM release profile better. The dissolution model could fit release profiles of PCTM best than Weibull model and first order model, which was formulated by to assume that the dissolution of PCTM crystals was considered the rate-controlling mechanism of drug release.
引文
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