基于壳聚糖PLGA纳米载体的构建及其水解释药研究
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摘要
壳聚糖和PLGA两种生物可降解聚合物作为纳米载体用于抗癌药物的包载和肿瘤靶向治疗已经成为近年来研究的热点，作为两种生物医用材料，壳聚糖和PLGA作为纳米载体各有特点，PLGA良好的成球性，包载率和生物安全性使其已经用于各种临床药物载体的研究，而其相对较高的疏水性、较高的药物突释和较低的靶向性却在一定程度上则限制了其应用，经研究，由于壳聚糖的亲水性和活性氨基的存在，通过壳聚糖的修饰可以改善PLGA纳米载体的细胞黏附性和缓释性。本文通过共价修饰的方法合成了壳聚糖-PLGA共聚物，利用超声自组装法制备了壳聚糖-PLGA纳米载体（G-NPs），以传统乳化方法建立的壳聚糖-PLGA纳米载体（C-NPs）和空白的PLGA纳米载体为参照，对这种新型结构的纳米载体的理化性质、表面结构、生物相容性、水解稳定性、药物缓释性和细胞摄取进行了系统研究。
通过乳化法制备了PLGANPs；以此为基础，在EDC和NHS的活化下，用壳聚糖对PLGANPs进行了表面接枝共聚，得到了表面修饰的C-NPs；以PLGA和壳聚糖两种聚合物为单体，通过EDC和NHS活化，将得到接枝共聚物超声自组装，得到了均一结构的G-NPs；制备得到的三种纳米载体，经红外光谱（FTIR）、核磁共振波普（~1HNMR）、元素分析、透射电镜（TEM）检测，验证了接枝共聚物的成功合成，元素分析表明采用直接催化反应的G-NPs中PLGA的取代度为11.83%，要高于乳化方法制备得到的C-NPs的7.62%；透射电镜观察得到的纳米粒子均呈完整的球形，具有不同的结构形态，三种纳米粒子的平均粒径在200nm左右，均呈现出良好的多分散性；利用荧光光谱分析测定了G-NPs的临界聚集浓度（CAC），讨论了G-NPs的自组装特性，得出分子间的氢键及疏水作用是促使G-NPs在水相中进行纳米自组装的主要作用力。
对三种纳米载体生物相容性研究采用了溶血试验、蛋白吸附实验和细胞毒性试验来评价。三种纳米材料的溶血率均低于5%，蛋白吸附水平随着纳米粒子浓度的增加而增大，但仍处于较低的水平，当纳米溶液浓度范围是13-800μg/ml时，三种纳米粒子分别与MCF-7细胞孵育24h和48h后，均未对MCF-7细胞的增殖产生显著影响，表明，三种纳米粒子对MCF-7细胞是没有毒性的。生物相容性实验证明，C-NPs和G-NPs都具有良好的生物相容性。
以抗癌药物阿霉素为药物模型，对纳米载体的体外药物包载和释药进行了研究，G-NPs和PLGA纳米载体表现出较好的药物载药量和包载效率。而通过体外释药研究发现，壳聚糖修饰PLGA后制备得到的C-NPs和G-NPs，相比于单纯的PLGANPs，降低了起始阶段的药物突释，但在突释完成后，C-NPs和G-NPs表现出了较好的药物累计释放效果，而且合成的G-NPs相对于传统方法制备的C-NPs，表现出12h较低的突释和72h较高的药物累积释放量，表现出更好的药物缓释性。
利用UHPLC技术检测研究了三种纳米载体中PLGA的水解机制，壳聚糖修饰的C-NPs和G-NPs水解速率要明显高于未修饰的PLGA纳米粒子，G-NPs由于其自组装的均一结构，使其相对于内部完全为疏水PLGA的C-NPs而言，更有利于PLGA的水解，呈现比C-NPs略高的水解速率。通过激光粒度仪对纳米粒子粒径和粒径分布以及TEM形态观察，进一步验证了PLGA纳米载体的水解机制，发现纳米粒子的形态随着水解时间的延长，粒径和形态发生了明显的变化。
以人乳腺癌细胞MCF-7为模型细胞对荧光标记纳米载体的摄取和生长抑制情况进行了研究，壳聚糖修饰的两种纳米粒子C-NPs和G-NPs表现出良好的细胞黏附性，通过荧光显微镜观察，均能有效的被MCF-7细胞摄取，而两种壳聚糖修饰的纳米载体的摄取效率无显著差异。细胞生长抑制的定量测定表明，载药后C-NPs和G-NPs在低浓度1-4μg/ml时，具有优于游离阿霉素和载药PLGA纳米载体的肿瘤细胞生长抑制率，另外载药纳米载体对MCF-7细胞生长的抑制具有一定的时间和浓度依赖性。
综上所述，新制备的G-NPs纳米载体相比于C-NPs和PLGANPs，由于制备工艺和载体结构的差异，表现出较高的载药量、包封率和较低的突释性；而且受较高的水解速率的影响，G-NPs在72h后表现出较高的药物累计释放量，说明作为一种新型的纳米药物载体，其在生物医药领域用于抗癌药物的包载和释放具有更好的高效性和低毒性，结果表明，制备得到的G-NPs纳米载体在包载疏水抗癌药物后，有潜力成为抑制肿瘤细胞生长的新型纳米载体。
Chitosan and Poly D,L-lactide-co-glycolide(PLGA)-based nano-materials have been successfully developed as drug delivery systems due to sustained drug-release property. PLGA-based nanoparticulate formulations, designed to bead ministered orally, topically, subcutaneously, or transmucosally have the advantage of supplying a continuous amount of drug over a long period of time. However, the non-specific interaction with cells and proteins and lack of suitable function groups for efficient covalent conjugation obstructed its application. Physical and chemical modification of PLGA nanoparticles were studied for practical requirements. Chitosan, as a natural biodegradable copolymer of N-acetyl glucosamine and D-glucosamine, has been widely used in pharmaceutical and drug delivery systems for its favorable biological properties, such as biodegradability, biocompatibility, low toxicity, hemostatic, bacteriostatic, fungistatic, anticancerogen, and anticholesteremic properties. Modification of reactive groups (-NH2) in chitosan molecule such as carboxymethylation and quaternary ammonium salt modification could improve its water solubility and biocampatibility.
PLGA nanoparticles were surface modified with chitosan by adsorption or covalent binding, both of which involved emulsification solvent evaporation and showed a unitary structure. The surface-modified structure of CHS-PLGA nanoparticles limited its applications in drug encapsulation and delivery. In order to improve the preparation and properties of CHS-PLGA nanoparticles, novel self-assembeled CHS-PLGA nanoparticles were prepared and studied.
In the present study, surfaced modified Chitosan-PLGA nanoparticles (C-NPs) and self-assembled chitosan-PLGA nanoparticles (G-NPs) were prepared. The naked PLGA NPs were served as control. Three kinds of differently structured nanoparticles were prepared and characterized by the laser light scattering technique, transmission electron microscopy (TEM), FT-IR spectroscopy and elemental analysis. Successful conjugation of chitosan to the PLGA particles was confirmed by FT-IR spectroscopy and elemental analysis. These nanoparticles all showed regularly spherical shape with mean diameters as191.3±3.6nm,211.9±13.2nm and187.5±17.6nm for PLGA NPs, C-NPs and G-NPs, respectively. Their zeta potentials were-22.4±1.31mV,-8.7±0.45mV,-3.1±0.12mV, respectively.
The hydrolytic erosion of PLGA, C-NPs and G-NPs and its influence on the release of DOX from those differently structured nanoparticles under acidic (pH3.8) and physiological (pH7.4) conditions were investigated. The process of hydrolytic erosion of the nanoparticles with time was evaluated by ultra high-pressure liquid chromatographic (UHPLC) analysis. Both C-NPs (15.3%PLGA remained after two weeks, pH7.4) and G-NPs (3.7%PLGA remained after two weeks, pH7.4) had higher hydrolysis rate than PLGA NPs (18.4%PLGA remained after6weeks, pH7.4), with G-NPs showing the highest rate in hydrolysis due to the incorporation of chitosan and its self-assembled structure. Self-assembling properties and controllable biodegradability of G-NPs indicated that it could be a promising drug delivery carrier for tumor drug delivery.
Doxorubicin (DOX) was efficiently loaded into the nanoparticles and showed sustained release in PBS at different pH. PLGA NPs had higher drug-loading content (DL%) and encapsulation efficiency (EE%) for its hydrophobic property and unmodified structure. At pH7.4, the burst release of PLGA particles at12h was57.28%, while it was43.44%and40.47%for C-NPs and G-NPs, respectively. The cumulative release rate of DOX from PLGA NPs, C-NPs and G-NPs after72h was60.03%,56.56%and62.85%, respectively. Presence of chitosan in the C-NPs reduced the burst release of the drug and accelerated the erosion rate of nanoparticles. Of the three kinds of nanoparticles, G-NPs had the fastest erosion rate in PBS for its homogenous structure, which lead to the highest the cumulative release rate of DOX. And the nanoparticles showed increased erosion rate and cumulative drug release at lower pH. The release profile of DOX from nanoparticles was closely related to nanoparticle erosion except for the initial burst release.
Furthermore, the biocompatibility of NPs was also investigated. Three kinds of nanoparticles showed low hemolysis rate and BSA adsorption rate. MTT assay showed that they were nontoxic and biocompatible to MCF-7cells.
The in vitro cellular uptake and growth inhibition of C-NPs and G-NPs were studied. Both the fluorescence microscopy and quantitative determination showed that C-NPs and G-NPs can be effectively endocytosed by MCF-7cells, while no significant difference in uptake efficiency of two nanoparticles. The quantitative determination of cell growth inhibition showed that the drug-loaded C-NPs and G-NPs in low concentrations1-4μg/ml, had higher cell growth inhibition rate than free doxorubicin and drug-loaded PLGA nanoparticles carrier. The drug-loaded nanoparticles of growth inhibition for MCF-7cells were time and concentration dependent. The in vitro experimental results demonstrated that G-NPs were favorable for tumor cell phagocytosis and drug control release.
Based on the above considerations, G-NPs have good biocompatibility and sustained drug release property, and drug-loaded nanoparticles show better inhibition to cancer cells than DOX in vitro, which revealed the promising potential as carriers for antitumor agents.
通过乳化法制备了PLGANPs；以此为基础，在EDC和NHS的活化下，用壳聚糖对PLGANPs进行了表面接枝共聚，得到了表面修饰的C-NPs；以PLGA和壳聚糖两种聚合物为单体，通过EDC和NHS活化，将得到接枝共聚物超声自组装，得到了均一结构的G-NPs；制备得到的三种纳米载体，经红外光谱（FTIR）、核磁共振波普（~1HNMR）、元素分析、透射电镜（TEM）检测，验证了接枝共聚物的成功合成，元素分析表明采用直接催化反应的G-NPs中PLGA的取代度为11.83%，要高于乳化方法制备得到的C-NPs的7.62%；透射电镜观察得到的纳米粒子均呈完整的球形，具有不同的结构形态，三种纳米粒子的平均粒径在200nm左右，均呈现出良好的多分散性；利用荧光光谱分析测定了G-NPs的临界聚集浓度（CAC），讨论了G-NPs的自组装特性，得出分子间的氢键及疏水作用是促使G-NPs在水相中进行纳米自组装的主要作用力。
对三种纳米载体生物相容性研究采用了溶血试验、蛋白吸附实验和细胞毒性试验来评价。三种纳米材料的溶血率均低于5%，蛋白吸附水平随着纳米粒子浓度的增加而增大，但仍处于较低的水平，当纳米溶液浓度范围是13-800μg/ml时，三种纳米粒子分别与MCF-7细胞孵育24h和48h后，均未对MCF-7细胞的增殖产生显著影响，表明，三种纳米粒子对MCF-7细胞是没有毒性的。生物相容性实验证明，C-NPs和G-NPs都具有良好的生物相容性。
以抗癌药物阿霉素为药物模型，对纳米载体的体外药物包载和释药进行了研究，G-NPs和PLGA纳米载体表现出较好的药物载药量和包载效率。而通过体外释药研究发现，壳聚糖修饰PLGA后制备得到的C-NPs和G-NPs，相比于单纯的PLGANPs，降低了起始阶段的药物突释，但在突释完成后，C-NPs和G-NPs表现出了较好的药物累计释放效果，而且合成的G-NPs相对于传统方法制备的C-NPs，表现出12h较低的突释和72h较高的药物累积释放量，表现出更好的药物缓释性。
利用UHPLC技术检测研究了三种纳米载体中PLGA的水解机制，壳聚糖修饰的C-NPs和G-NPs水解速率要明显高于未修饰的PLGA纳米粒子，G-NPs由于其自组装的均一结构，使其相对于内部完全为疏水PLGA的C-NPs而言，更有利于PLGA的水解，呈现比C-NPs略高的水解速率。通过激光粒度仪对纳米粒子粒径和粒径分布以及TEM形态观察，进一步验证了PLGA纳米载体的水解机制，发现纳米粒子的形态随着水解时间的延长，粒径和形态发生了明显的变化。
以人乳腺癌细胞MCF-7为模型细胞对荧光标记纳米载体的摄取和生长抑制情况进行了研究，壳聚糖修饰的两种纳米粒子C-NPs和G-NPs表现出良好的细胞黏附性，通过荧光显微镜观察，均能有效的被MCF-7细胞摄取，而两种壳聚糖修饰的纳米载体的摄取效率无显著差异。细胞生长抑制的定量测定表明，载药后C-NPs和G-NPs在低浓度1-4μg/ml时，具有优于游离阿霉素和载药PLGA纳米载体的肿瘤细胞生长抑制率，另外载药纳米载体对MCF-7细胞生长的抑制具有一定的时间和浓度依赖性。
综上所述，新制备的G-NPs纳米载体相比于C-NPs和PLGANPs，由于制备工艺和载体结构的差异，表现出较高的载药量、包封率和较低的突释性；而且受较高的水解速率的影响，G-NPs在72h后表现出较高的药物累计释放量，说明作为一种新型的纳米药物载体，其在生物医药领域用于抗癌药物的包载和释放具有更好的高效性和低毒性，结果表明，制备得到的G-NPs纳米载体在包载疏水抗癌药物后，有潜力成为抑制肿瘤细胞生长的新型纳米载体。
Chitosan and Poly D,L-lactide-co-glycolide(PLGA)-based nano-materials have been successfully developed as drug delivery systems due to sustained drug-release property. PLGA-based nanoparticulate formulations, designed to bead ministered orally, topically, subcutaneously, or transmucosally have the advantage of supplying a continuous amount of drug over a long period of time. However, the non-specific interaction with cells and proteins and lack of suitable function groups for efficient covalent conjugation obstructed its application. Physical and chemical modification of PLGA nanoparticles were studied for practical requirements. Chitosan, as a natural biodegradable copolymer of N-acetyl glucosamine and D-glucosamine, has been widely used in pharmaceutical and drug delivery systems for its favorable biological properties, such as biodegradability, biocompatibility, low toxicity, hemostatic, bacteriostatic, fungistatic, anticancerogen, and anticholesteremic properties. Modification of reactive groups (-NH2) in chitosan molecule such as carboxymethylation and quaternary ammonium salt modification could improve its water solubility and biocampatibility.
PLGA nanoparticles were surface modified with chitosan by adsorption or covalent binding, both of which involved emulsification solvent evaporation and showed a unitary structure. The surface-modified structure of CHS-PLGA nanoparticles limited its applications in drug encapsulation and delivery. In order to improve the preparation and properties of CHS-PLGA nanoparticles, novel self-assembeled CHS-PLGA nanoparticles were prepared and studied.
In the present study, surfaced modified Chitosan-PLGA nanoparticles (C-NPs) and self-assembled chitosan-PLGA nanoparticles (G-NPs) were prepared. The naked PLGA NPs were served as control. Three kinds of differently structured nanoparticles were prepared and characterized by the laser light scattering technique, transmission electron microscopy (TEM), FT-IR spectroscopy and elemental analysis. Successful conjugation of chitosan to the PLGA particles was confirmed by FT-IR spectroscopy and elemental analysis. These nanoparticles all showed regularly spherical shape with mean diameters as191.3±3.6nm,211.9±13.2nm and187.5±17.6nm for PLGA NPs, C-NPs and G-NPs, respectively. Their zeta potentials were-22.4±1.31mV,-8.7±0.45mV,-3.1±0.12mV, respectively.
The hydrolytic erosion of PLGA, C-NPs and G-NPs and its influence on the release of DOX from those differently structured nanoparticles under acidic (pH3.8) and physiological (pH7.4) conditions were investigated. The process of hydrolytic erosion of the nanoparticles with time was evaluated by ultra high-pressure liquid chromatographic (UHPLC) analysis. Both C-NPs (15.3%PLGA remained after two weeks, pH7.4) and G-NPs (3.7%PLGA remained after two weeks, pH7.4) had higher hydrolysis rate than PLGA NPs (18.4%PLGA remained after6weeks, pH7.4), with G-NPs showing the highest rate in hydrolysis due to the incorporation of chitosan and its self-assembled structure. Self-assembling properties and controllable biodegradability of G-NPs indicated that it could be a promising drug delivery carrier for tumor drug delivery.
Doxorubicin (DOX) was efficiently loaded into the nanoparticles and showed sustained release in PBS at different pH. PLGA NPs had higher drug-loading content (DL%) and encapsulation efficiency (EE%) for its hydrophobic property and unmodified structure. At pH7.4, the burst release of PLGA particles at12h was57.28%, while it was43.44%and40.47%for C-NPs and G-NPs, respectively. The cumulative release rate of DOX from PLGA NPs, C-NPs and G-NPs after72h was60.03%,56.56%and62.85%, respectively. Presence of chitosan in the C-NPs reduced the burst release of the drug and accelerated the erosion rate of nanoparticles. Of the three kinds of nanoparticles, G-NPs had the fastest erosion rate in PBS for its homogenous structure, which lead to the highest the cumulative release rate of DOX. And the nanoparticles showed increased erosion rate and cumulative drug release at lower pH. The release profile of DOX from nanoparticles was closely related to nanoparticle erosion except for the initial burst release.
Furthermore, the biocompatibility of NPs was also investigated. Three kinds of nanoparticles showed low hemolysis rate and BSA adsorption rate. MTT assay showed that they were nontoxic and biocompatible to MCF-7cells.
The in vitro cellular uptake and growth inhibition of C-NPs and G-NPs were studied. Both the fluorescence microscopy and quantitative determination showed that C-NPs and G-NPs can be effectively endocytosed by MCF-7cells, while no significant difference in uptake efficiency of two nanoparticles. The quantitative determination of cell growth inhibition showed that the drug-loaded C-NPs and G-NPs in low concentrations1-4μg/ml, had higher cell growth inhibition rate than free doxorubicin and drug-loaded PLGA nanoparticles carrier. The drug-loaded nanoparticles of growth inhibition for MCF-7cells were time and concentration dependent. The in vitro experimental results demonstrated that G-NPs were favorable for tumor cell phagocytosis and drug control release.
Based on the above considerations, G-NPs have good biocompatibility and sustained drug release property, and drug-loaded nanoparticles show better inhibition to cancer cells than DOX in vitro, which revealed the promising potential as carriers for antitumor agents.
引文
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