载阿霉素PLGA纳米微球的制备及其对肝癌细胞的毒性作用研究
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摘要
肝癌是常见的病死率较高的恶性肿瘤,全身化疗是中晚期癌症患者的主要治疗方法,但全身化疗药物选择性低,毒副反应大,疗效差。载药纳米药物投递系统是近年来新兴的药物靶向运送制剂,它借助于安全无毒的各种运送载体,采用特殊工艺方法制备纳米级别的药物微球;纳米药物微球具有靶向传递、可控缓慢释放、增强药效及降低毒副反应等特点,有望成为癌症组织的靶向化疗制剂。本课题旨在制备载阿霉素纳米微球,研究探讨其性质表征、制备工艺及体外细胞毒作用,为纳米药物载体制剂的研究及开发提供一定的实验基础。
目的
制备载阿霉素乳酸羟基乙酸共聚物PLGA纳米微球(ADM-PLGA-NP),分析表征其一般理化性质及缓释特点,探讨研究其对体外培养的肝癌细胞系HepG2的细胞毒作用。
方法
1.采用改良的W/O/W复乳溶剂蒸发法制备ADM-PLGA-NP,场发射扫描电镜观察微球形态,激光衍射粒度分析仪检测微球粒径分布及多分散性,紫外分光光度法计算载药率及包封率,体外药物释放实验考察微球对ADM的缓释规律;
2. HepG2细胞分别与ADM原药和载药纳米微球ADM-PLGA-NP(根据体外药物释药曲线计算出释药量)共培养一定时间后,相差倒置显微镜观察给药后的细胞形态的变化,噻唑蓝(MTT)比色法评价ADM-PLGA-NP的细胞毒作用,荧光显微镜观察细胞对ADM-PLGA-NP的吞噬摄取,流式细胞术半定量细胞内的阿霉素药物含量,研究ADM原药和载药纳米微球ADM-PLGA-NP的细胞摄取量及细胞毒性差异。
结果
1.制备的ADM-PLGA-NP外观呈圆整球形,无明显粘连;平均粒径约237±12.7nm,大小均匀,分布范围窄,多分散性指数为0.022;载药量及包封率分别为1.42±0.67 %和23.82±8.34 %;药物在体外缓慢释放,12h内呈突释,突释量达药物总量的55%,5d累积释放量达85%。
2.ADM原药和载药纳米微球ADM-PLGA-NP分别与HepG2细胞共培养后,相差倒置显微镜观察示细胞贴壁能力减弱,胞质固缩,甚至死亡;MTT实验示空白微球对HepG2细胞的平均增殖抑制率为5.98±2.96%;ADM-PLGA-NP和ADM原药均能抑制HepG2细胞增殖,ADM原药的细胞抑制增殖率较ADM-PLGA-NP低(p<0.05);荧光显微镜观察到ADM-PLGA-NP被细胞吞噬后ADM发出红色荧光;流式细胞术半定量显示,ADM-PLGA-NP较ADM原药在细胞内有更强的ADM药物分子荧光强度。
结论
利用复乳溶剂蒸发法制备的ADM-PLGA-NP性质稳定,表征满意,具有药物缓释性。ADM-PLGA-NP可以被HepG2细胞吞噬摄取,ADM从微球中缓慢释放,较ADM原药可更有效地抑制肝癌细胞的生长。ADM-PLGA-NP有望成为一种新型的药物化疗制剂。
HCC is a common malignant tumor with a high mortality rate, but the main treatment in advanced HCC patients, systemic chemotherapy, has a poor efficacy due to the low selectivity and toxicity of chemotherapy drugs. Drug-loaded nanoparticle delivery system is very popular in transporting drug-targeting agents in recent years. The system is prepared by incorporating drugs with a variety of non-toxic carriers, producing nano-level microspheres with targeted delivery. With controlled drug release, enhanced efficacy, reduced side effects and low toxicity characteristics, the system is expected to be a efficient targeted anti-cancer chemotherapeutic agents. This study includes the preparation, characterization and in vitro cytotoxicity evaluation of adriamycin-loaded nanoparticles. More importantly, the purpose of this study is to provide some experimental basis for the development of drug-loaded nanoparticle delivery system.
Objective
This study is aimed to prepare and characterize adriamycin-loaded PLGA copolymer nanoparticles(ADM-PLGA-NP) and investigate the cytotoxicity of released adriamycin on human hepatocellular carcinoma cell line HepG2.
Methods
1. PLGA nanoparticles containing adriamycin were formulated by w/o/w improved emulsification-solvent evaporation method. The morphology was observed by scanning electron microscopy (SEM) and the size distribution was investigated by laser diffraction analyzer. The encapsulating efficiency of ADM was determined by ultraviolet spectrophotometry. ADM-PLGA-NP was put in a dialysis bag to observe the releasing characteristics of ADM from ADM-PLGA nanoparticles in vitro.
2. Hepatocellular carcinoma cell line HepG2 was cultured with ADM-PLGA nanoparticles of different concentrations (the released drug doses were calculated according to the release curve in vitro) and the original ADM drug for a certain amount of time. Then, the morphology of HepG2 cells were photographed by using phase-contrast microscope. MTT assay was used to observe the cell growth inhibition rate. The cellular uptake of nanoparticles was evaluated by fluorescence microscopy. Flow cytometry was employed to quantify red fluorescence intensity in HepG2 cells.
Results
1. The prepared ADM-PLGA nanoparticles were of spherical or elliptical shape with average size of 237±12.7nm. The loading efficiency and entrapment efficiency were about 1.42±0.67% and 23.82±8.34%, respectively. The releasing test in vitro manifested that over 85 percent of ADM encapsulated in ADM-PLGA nanoparticles was sustained released in about 5 days, with a burst release in the first 12 hours.
2. Co-culture of HepG2 cells with ADM-PLGA-NPs showed that the cells were extremely spreaded with weakening cell adhesion and cytoplasmic condensation. MTT test showed that the average cell growth inhibition rate of blank nanoparticles was 5.98±2.96%; while the cell growth inhibition rate of ADM-PLGA-NP was higher than that of original drug (p <0.05). The cellular uptake of nanoparticles was observed by fluorescence microscopy. Flow cytometry illustrated that red fluorescence intensity in HepG2 cells incubated with ADM-PLGA-NP was stronger than that of incubated with original drug.
Conclusions
The ADM-loaded PLGA nanoparticles formulated by w/o/w emulsification solvent evaporation method had satisfactory characterization with sustained release of ADM drugs. ADM-PLGA-NP can be swallowed by HepG2 cells and showed more significant effects in inhibiting the growth of HepG2 cells than the original ADM drug did. ADM-PLGA-NPs are expected to become a new targeting chemotherapy agents.
目的
制备载阿霉素乳酸羟基乙酸共聚物PLGA纳米微球(ADM-PLGA-NP),分析表征其一般理化性质及缓释特点,探讨研究其对体外培养的肝癌细胞系HepG2的细胞毒作用。
方法
1.采用改良的W/O/W复乳溶剂蒸发法制备ADM-PLGA-NP,场发射扫描电镜观察微球形态,激光衍射粒度分析仪检测微球粒径分布及多分散性,紫外分光光度法计算载药率及包封率,体外药物释放实验考察微球对ADM的缓释规律;
2. HepG2细胞分别与ADM原药和载药纳米微球ADM-PLGA-NP(根据体外药物释药曲线计算出释药量)共培养一定时间后,相差倒置显微镜观察给药后的细胞形态的变化,噻唑蓝(MTT)比色法评价ADM-PLGA-NP的细胞毒作用,荧光显微镜观察细胞对ADM-PLGA-NP的吞噬摄取,流式细胞术半定量细胞内的阿霉素药物含量,研究ADM原药和载药纳米微球ADM-PLGA-NP的细胞摄取量及细胞毒性差异。
结果
1.制备的ADM-PLGA-NP外观呈圆整球形,无明显粘连;平均粒径约237±12.7nm,大小均匀,分布范围窄,多分散性指数为0.022;载药量及包封率分别为1.42±0.67 %和23.82±8.34 %;药物在体外缓慢释放,12h内呈突释,突释量达药物总量的55%,5d累积释放量达85%。
2.ADM原药和载药纳米微球ADM-PLGA-NP分别与HepG2细胞共培养后,相差倒置显微镜观察示细胞贴壁能力减弱,胞质固缩,甚至死亡;MTT实验示空白微球对HepG2细胞的平均增殖抑制率为5.98±2.96%;ADM-PLGA-NP和ADM原药均能抑制HepG2细胞增殖,ADM原药的细胞抑制增殖率较ADM-PLGA-NP低(p<0.05);荧光显微镜观察到ADM-PLGA-NP被细胞吞噬后ADM发出红色荧光;流式细胞术半定量显示,ADM-PLGA-NP较ADM原药在细胞内有更强的ADM药物分子荧光强度。
结论
利用复乳溶剂蒸发法制备的ADM-PLGA-NP性质稳定,表征满意,具有药物缓释性。ADM-PLGA-NP可以被HepG2细胞吞噬摄取,ADM从微球中缓慢释放,较ADM原药可更有效地抑制肝癌细胞的生长。ADM-PLGA-NP有望成为一种新型的药物化疗制剂。
HCC is a common malignant tumor with a high mortality rate, but the main treatment in advanced HCC patients, systemic chemotherapy, has a poor efficacy due to the low selectivity and toxicity of chemotherapy drugs. Drug-loaded nanoparticle delivery system is very popular in transporting drug-targeting agents in recent years. The system is prepared by incorporating drugs with a variety of non-toxic carriers, producing nano-level microspheres with targeted delivery. With controlled drug release, enhanced efficacy, reduced side effects and low toxicity characteristics, the system is expected to be a efficient targeted anti-cancer chemotherapeutic agents. This study includes the preparation, characterization and in vitro cytotoxicity evaluation of adriamycin-loaded nanoparticles. More importantly, the purpose of this study is to provide some experimental basis for the development of drug-loaded nanoparticle delivery system.
Objective
This study is aimed to prepare and characterize adriamycin-loaded PLGA copolymer nanoparticles(ADM-PLGA-NP) and investigate the cytotoxicity of released adriamycin on human hepatocellular carcinoma cell line HepG2.
Methods
1. PLGA nanoparticles containing adriamycin were formulated by w/o/w improved emulsification-solvent evaporation method. The morphology was observed by scanning electron microscopy (SEM) and the size distribution was investigated by laser diffraction analyzer. The encapsulating efficiency of ADM was determined by ultraviolet spectrophotometry. ADM-PLGA-NP was put in a dialysis bag to observe the releasing characteristics of ADM from ADM-PLGA nanoparticles in vitro.
2. Hepatocellular carcinoma cell line HepG2 was cultured with ADM-PLGA nanoparticles of different concentrations (the released drug doses were calculated according to the release curve in vitro) and the original ADM drug for a certain amount of time. Then, the morphology of HepG2 cells were photographed by using phase-contrast microscope. MTT assay was used to observe the cell growth inhibition rate. The cellular uptake of nanoparticles was evaluated by fluorescence microscopy. Flow cytometry was employed to quantify red fluorescence intensity in HepG2 cells.
Results
1. The prepared ADM-PLGA nanoparticles were of spherical or elliptical shape with average size of 237±12.7nm. The loading efficiency and entrapment efficiency were about 1.42±0.67% and 23.82±8.34%, respectively. The releasing test in vitro manifested that over 85 percent of ADM encapsulated in ADM-PLGA nanoparticles was sustained released in about 5 days, with a burst release in the first 12 hours.
2. Co-culture of HepG2 cells with ADM-PLGA-NPs showed that the cells were extremely spreaded with weakening cell adhesion and cytoplasmic condensation. MTT test showed that the average cell growth inhibition rate of blank nanoparticles was 5.98±2.96%; while the cell growth inhibition rate of ADM-PLGA-NP was higher than that of original drug (p <0.05). The cellular uptake of nanoparticles was observed by fluorescence microscopy. Flow cytometry illustrated that red fluorescence intensity in HepG2 cells incubated with ADM-PLGA-NP was stronger than that of incubated with original drug.
Conclusions
The ADM-loaded PLGA nanoparticles formulated by w/o/w emulsification solvent evaporation method had satisfactory characterization with sustained release of ADM drugs. ADM-PLGA-NP can be swallowed by HepG2 cells and showed more significant effects in inhibiting the growth of HepG2 cells than the original ADM drug did. ADM-PLGA-NPs are expected to become a new targeting chemotherapy agents.
引文
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