新型季铵盐壳聚糖纳米载药体系的研究
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摘要
对天然多糖壳聚糖进行了改性,制备了一种能溶于中性水的壳聚糖衍生物N,N,N-三甲基壳聚糖盐酸盐(TMC)。根据分别带有正、负电荷的聚电解质溶液发生复凝聚的原理,使用TMC溶液与带负电荷的羧甲基壳聚糖(CMC)及肝素(Hep)溶液,分别制备了两种新型的纳米粒子TMC/CMC、TMC/Hep载药体系。
使用红外光谱、激光散射仪、透射电镜、原子力显微镜等手段对制备的纳米粒子形成条件、纳米粒子的粒径、粒径分布、表面电位、表面形貌、pH值及离子浓度的稳定性等进行了表征。结果表明:该纳米粒子大致为球形,粒径在150～600 nm之间,粒径分布很窄,表面通常带正电荷。粒径和表面电位可以通过改变制备条件来调节。
探讨并优化了TMC/CMC、TMC/Hep两种纳米粒子作为药物载体的制备条件,考察了影响药物包封率、体外释放行为的因素。结果显示,两种纳米粒子在负载药物后粒径减小。两种纳米粒子对牛血清蛋白、阿霉素的包封能力均与TMC浓度、TMC季铵化程度等因素相关;包封率和包封量可以通过改变影响因素来调节。体外释放结果显示,两种纳米载药体系均显示出初期释放快速,后期释放缓慢的特点。释放速率也可以调节。阿霉素的体外释放曲线与一级动力学模型和Ritger-Pappas模型的拟合精度较高。
用MTT法考察了游离阿霉溶液和负载阿霉素的纳米粒子溶液对HepG2细胞的抑制作用和在小鼠体内的药物代谢动力学行为。结果表明,阿霉素包封于纳米粒子后活性没有降低,可在更长的时间内更有效地作用于癌细胞。与游离阿霉素溶液相比,负载阿霉素的TMC/Hep纳米粒子溶液在小鼠血液中的半衰期延长,在肝脏和脾脏的分布增加,而在心脏中的浓度降低。
为了考察纳米粒子被细胞摄取的过程以及体内分布,在TMC上接枝了异硫氰酸荧光素(FITC),并以此制备了TMC-g-FITC/CMC,TMC-g-FITC/Hep两种新型的纳米粒子荧光探针。考察了HepG 2细胞摄取纳米粒子的影响因素,用激光共聚焦显微镜观察了HepG 2细胞对纳米荧光探针对的摄取过程,经小鼠尾静脉注射观察其在体内的分布。结果表明,HepG2细胞对这两种纳米荧光探针的摄取能力与TMC浓度、细胞培养的温度相关,随时间延长,纳米粒子向细胞核聚集。小鼠体内实验显示,该纳米粒子有一定的肝靶向性。
评价了TMC及其纳米粒子对质粒DNA(pDNA)的负载及保护能力,考察了其纳米复合物对HepG 2细胞的转染能力。结果表明,TMC12.11与pDNA的质量比为10:1时,在48 h达到最高的转染效率。而TMC/CMC、TMC/Hep纳米粒子对pDNA的载体保护能力增强,但对HepG2细胞的最高转染效率出现在72h。
In this study, a chitosan derivative N, N, N-trimethyl chitosan chloride (TMC) was synthesized by the reaction between methyl iodide and chitosan. Based on contrarily electrostatic interaction, two novel type of nanoparticles were formed, which are TMC/CMC or TMC/Hep nanoparticles.
The forming condition, the size, polydispersity, zeta potential, morphology and the stability of the nanoparticles were measured with IR, dynamic laser scattering, transmission electron microscopy and atom force microscopy. It is found that the nanoparticles were global and the size was between 150-600 nm, the polydispersity was narrow, and mostly which were positive. The size and zeta potential of the nanoparticles were adjustable.
As a carrier for the anticancer drug, doxorubicin (DOX), it was found that the size of the drug loaded nanoparticles was smaller than blank nanoparticles. The loading efficiency and the loading capacity of the nanoparticles were related with the concentration of TMC and the quaternization degree of TMC, and could be adjusted. And the drug released in vitro showed an initial fast release phase, followed by a platform time, and had a better fitting precision with first order elimination kinetics and Ritger-Pappas model.
MTT assay was used to test the inhibited effect of the DOX loaded nanoparticles on HepG 2 cells. It was showed that they had a slightly decreased cytotoxicity to free DOX within 24h, while with time extended its toxicity reinforced. Animal study indicated that the half-time of DOX-loaded nanoparticles prolonged and the DOX concentration in the heart was decreased and increased in the liver.
In order to observe the cell uptake of nanoparticles, we synthesized the TMC-g-FITC, and composed two novel nono-sized fluorescent probes: TMC-g-FITC/CMC and TMC-g-FITC/Hep nanoparticles. Uptake of the nanoparticles by HepG 2 cells was observed by inverted fluorescence microscope and confocal laser scanning microscopy. it was found that the nanoparticles had little toxic to the cells, the culture tempreture and the concentration of TMC-g-FITC affected the uptake process, and the fluorescence nanoparticles first aggregated across the cells and then be absorptive by the cell and cell nucleus. And the fluorescence nanoparticles were accumulated at liver after injected from mice tail vein.
The pDNA loading, protecting and transfection capacity of TMC and its nanoparticles were evaluated, effective plasmid DNA carrier, it was discovered that both of them can protect the pDNA from being digested. 48h later after transfection, TMC12.11/pDNA nanoparticles has the highest transfection efficiency. However, to TMC/CMC/pDNA and TMC/Hep/pDNA nanoparticles, the time was 72h later.
使用红外光谱、激光散射仪、透射电镜、原子力显微镜等手段对制备的纳米粒子形成条件、纳米粒子的粒径、粒径分布、表面电位、表面形貌、pH值及离子浓度的稳定性等进行了表征。结果表明:该纳米粒子大致为球形,粒径在150～600 nm之间,粒径分布很窄,表面通常带正电荷。粒径和表面电位可以通过改变制备条件来调节。
探讨并优化了TMC/CMC、TMC/Hep两种纳米粒子作为药物载体的制备条件,考察了影响药物包封率、体外释放行为的因素。结果显示,两种纳米粒子在负载药物后粒径减小。两种纳米粒子对牛血清蛋白、阿霉素的包封能力均与TMC浓度、TMC季铵化程度等因素相关;包封率和包封量可以通过改变影响因素来调节。体外释放结果显示,两种纳米载药体系均显示出初期释放快速,后期释放缓慢的特点。释放速率也可以调节。阿霉素的体外释放曲线与一级动力学模型和Ritger-Pappas模型的拟合精度较高。
用MTT法考察了游离阿霉溶液和负载阿霉素的纳米粒子溶液对HepG2细胞的抑制作用和在小鼠体内的药物代谢动力学行为。结果表明,阿霉素包封于纳米粒子后活性没有降低,可在更长的时间内更有效地作用于癌细胞。与游离阿霉素溶液相比,负载阿霉素的TMC/Hep纳米粒子溶液在小鼠血液中的半衰期延长,在肝脏和脾脏的分布增加,而在心脏中的浓度降低。
为了考察纳米粒子被细胞摄取的过程以及体内分布,在TMC上接枝了异硫氰酸荧光素(FITC),并以此制备了TMC-g-FITC/CMC,TMC-g-FITC/Hep两种新型的纳米粒子荧光探针。考察了HepG 2细胞摄取纳米粒子的影响因素,用激光共聚焦显微镜观察了HepG 2细胞对纳米荧光探针对的摄取过程,经小鼠尾静脉注射观察其在体内的分布。结果表明,HepG2细胞对这两种纳米荧光探针的摄取能力与TMC浓度、细胞培养的温度相关,随时间延长,纳米粒子向细胞核聚集。小鼠体内实验显示,该纳米粒子有一定的肝靶向性。
评价了TMC及其纳米粒子对质粒DNA(pDNA)的负载及保护能力,考察了其纳米复合物对HepG 2细胞的转染能力。结果表明,TMC12.11与pDNA的质量比为10:1时,在48 h达到最高的转染效率。而TMC/CMC、TMC/Hep纳米粒子对pDNA的载体保护能力增强,但对HepG2细胞的最高转染效率出现在72h。
In this study, a chitosan derivative N, N, N-trimethyl chitosan chloride (TMC) was synthesized by the reaction between methyl iodide and chitosan. Based on contrarily electrostatic interaction, two novel type of nanoparticles were formed, which are TMC/CMC or TMC/Hep nanoparticles.
The forming condition, the size, polydispersity, zeta potential, morphology and the stability of the nanoparticles were measured with IR, dynamic laser scattering, transmission electron microscopy and atom force microscopy. It is found that the nanoparticles were global and the size was between 150-600 nm, the polydispersity was narrow, and mostly which were positive. The size and zeta potential of the nanoparticles were adjustable.
As a carrier for the anticancer drug, doxorubicin (DOX), it was found that the size of the drug loaded nanoparticles was smaller than blank nanoparticles. The loading efficiency and the loading capacity of the nanoparticles were related with the concentration of TMC and the quaternization degree of TMC, and could be adjusted. And the drug released in vitro showed an initial fast release phase, followed by a platform time, and had a better fitting precision with first order elimination kinetics and Ritger-Pappas model.
MTT assay was used to test the inhibited effect of the DOX loaded nanoparticles on HepG 2 cells. It was showed that they had a slightly decreased cytotoxicity to free DOX within 24h, while with time extended its toxicity reinforced. Animal study indicated that the half-time of DOX-loaded nanoparticles prolonged and the DOX concentration in the heart was decreased and increased in the liver.
In order to observe the cell uptake of nanoparticles, we synthesized the TMC-g-FITC, and composed two novel nono-sized fluorescent probes: TMC-g-FITC/CMC and TMC-g-FITC/Hep nanoparticles. Uptake of the nanoparticles by HepG 2 cells was observed by inverted fluorescence microscope and confocal laser scanning microscopy. it was found that the nanoparticles had little toxic to the cells, the culture tempreture and the concentration of TMC-g-FITC affected the uptake process, and the fluorescence nanoparticles first aggregated across the cells and then be absorptive by the cell and cell nucleus. And the fluorescence nanoparticles were accumulated at liver after injected from mice tail vein.
The pDNA loading, protecting and transfection capacity of TMC and its nanoparticles were evaluated, effective plasmid DNA carrier, it was discovered that both of them can protect the pDNA from being digested. 48h later after transfection, TMC12.11/pDNA nanoparticles has the highest transfection efficiency. However, to TMC/CMC/pDNA and TMC/Hep/pDNA nanoparticles, the time was 72h later.
引文
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