TNF-α拮抗肽缓释微球及其长循环纳米粒的研究
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摘要
肿瘤坏死因子α(tumor necrosis factor alpha, TNF-α)在类风湿关节炎、内毒性休克等疾病发生和发展中起重要作用,并导致较高死亡率。前期研究表明,TNF-α拮抗肽(Tumor Necrosis Factor alpha Blocking Peptide ,TNF-BP)生物效应明确,有可能成为抗TNF相关疾病的新型肽类药物。但是,TNF-BP稳定性差、生物半衰期短,难以直接应用于临床。本文分别以乳酸-羟基乙酸共聚物(poly (lactide-co–glycolic acid) , PLGA )和PEG修饰的PLGA ( polyethyleneglycol-modified poly ( d,l-lactide-co-glycolide),PEG-PLGA )为载体材料,制备了载TNF-BP的PLGA长效缓释微球和载TNF-BP的PEG-PLGA长循环纳米粒,为TNF-BP临床应用提供实验依据。主要开展了以下工作:
(1)研究了载TNF-BP的PLGA长效缓释微球。以TNF-BP为药物,PLGA为载体,通过二次乳化法制备了TNF-BP长效缓释微球,并对所制得的微球进行了表征评价。为了筛选配方的最佳条件,在单因素考察的基础上,通过正交表L16(45)的设计试验,考察了不同因素水平对微球载药量和包封率的影响。采用光学显微镜、扫描电子显微镜、激光散射仪等技术对PLGA微球进行了表征。
对制备的微球采用冷冻干燥技术制备TNF-BP长效缓释微球的冻干粉。通过冷冻干燥工艺的研究,评价了葡萄糖、蔗糖和甘露醇3种多元醇对微球冷冻干燥的影响。
对制备的载药微球进行体外释药研究,并对释药行为进行药物释放数学模型拟合。
(2)研究了载TNF-BP的PEG-PLGA长循环纳米粒。以TNF-BP为药物,PEG-PLGA为载体,通过溶剂挥发法制备具有长循环效能的TNF-BP长循环纳米粒,并对所制得的纳米粒进行了表征评价。为了筛选配方的最佳条件,考察了不同因素对纳米粒粒径及粒径分布的影响。采用透射电子显微镜、激光散射仪等技术对PEG-PLGA纳米粒进行了表征。
对制备的纳米粒进行体外释药研究,并对释药行为进行了药物释放数学模型拟合。
对制备的载药纳米粒进行了初步生物学效应的研究,采用流式细胞仪检测了腹腔巨噬细胞对PEG-PLGA纳米粒的吞噬作用,同时采用Western-blot研究了纳米粒对TNF-BP的保护作用。
通过以上研究获得了以下结果:
(1)通过二次乳化法,采用优化后的工艺制备所得PLGA微球,平均粒径为(10.23±0.03)μm,平均载药量为(13.39±0.29)%,平均药物包封率为(83.54±0.24%)。
(2)冷冻干燥对微球的形态和结构都会产生较大影响,因此必须加入冻干保护剂。在葡萄糖、蔗糖和甘露醇3种多元醇冻干保护剂中,3%的甘露醇具有较好的效果。
(3)TNF-BP微球具有良好的缓释效果,其体外释药行为符合双相动力学模型方程,回归方程为: Q = ?0 .010+38.856·(1-e~(-t/0.496))+27.96·(1-e~(-t/50.004))。
(4)通过溶剂挥发法采用优化后的工艺制备所得PEG-PLGA纳米粒,平均粒径为(80.8±0.6) nm;粒径分布为(0.073±0.034);平均Zeta电位为(-17.90±1.00) mV;平均载药量为(1.22±0.15%);平均药物包封率为(56.10±7.49)%。
(5)PEG-PLGA纳米粒体外释药24 h时,累计释放达到71.85%,表现出TNF-BP纳米粒释放效率极高,对于内毒素性休克引发的急性肺损伤具有极为重要的意义。纳米粒的体外释药符合双相动力学模型方程,回归方程为: Q = 0 .008+36.710·(1-e~(-t/0.134))+34.705·(1-e~(-t/2.580))。
(6)制备的PEG修饰的载药纳米粒能有效避免吞噬,达到长循环的目的,此外,长循环纳米粒对载附的药物TNF-BP具有很高的保护作用。
Tumor Necrosis Factor alpha blocking peptide (TNF-BP), a cycle-seven-peptide, which was shown to be capable to block the biological activities of TNF-α, can protect the joint from inflammol/Latory damage induced by rheumatoid arthritis and reduce the damage from Acute Lung Trauma induced by Endotoxic Shock. The major problem for the application of TNF-BP is that it is a small peptide with molecular weight about 1 kDa so that its half-life time in blood circulation is very short. These often results in low bioavailability. In order to overcome the problems, drug carriers are needed to sustained-release, control delivery and extend half-life of TNF-BP. Two novel drug carriers as sustained-release microspheres and long-circulating nanoparticles would be suitable for our purpose. Poly (lactide-co–glycolic acid) (PLGA), as a biocompatible and slowly degradable polymer, has been targeting, widely used in drug delivery systems, especially in drug-controlled release.
The dissertation consists of two parts. In partⅠ, the subject was to explore the methods of coupling TNF-BP to PLGA microspheres based on double emulsion process, and provide references for the study of targeting, sustained and controlled release delivery systems of TNF-BP. In order to gain the best parameters for preparing PLGA microspheres, the influences of different factors on average drug loading and average entrapment efficiency of PLGA microspheres were evaluated by orthogonal-designing method using L16(45) table. The physicochemical properties of PLGA microspheres were investigated in detail by using optical microscope, scanning electronic microscope (SEM) and laser dynamic scattering. The average particle size of PLGA microspheres was (10.23±0.026)μm. The average drug loading and the average entrapment efficiency were (13.39±0.286)%, (83.54±0.241) % respectively.
The lyophilized powders of TNF-BP-loaded PLGA microspheres were obtained in order to enhance the stability. Glucose, sucrose and mannitol were used as cryoprotectants in the freeze-drying process. Mannitol, concentration in 3%, was selected as the optimum cryoprotectant due to the minimum change of physicochemical properties of PLGA microspheres before and after freeze-drying process.
In vitro releasing property of TNF-BP PLGA microspheres was studied and the drug releasing performance was good. TNF-BP releasing from PLGA microspheres in vitro could be described by double phase dynamic model and could be described by the following equation: Q = ?0. 010+38.856·(1-e~(-t/0.496))+27.96·(1-e~(-t/50.004)).
In partⅡ, the subject was to explore the methods of coupling TNF-BP to polyethyleneglycol-modified poly ( d,l-lactide-co-glycolide ) ( PEG-PLGA ) nanoparticles based on solvent evaporation process, and provide references for the study of targeting, sustained and controlled release delivery systems of TNF-BP. In order to gain the best parameters for preparing PEG-PLGA nanoparticles, the influences of some factors on average particle size and polydispersity index (PDI) of PEG-PLGA nanoparticles such as the type of polymer, the polymer concentration, the type of emulsifiers and the emulsifier concentration were studied. The size, morphology and zeta potential of PEG-PLGA nanoparticles were investigated in detail by using transmission electronic microscope (TEM), Zeta potential analysis and laser dynamic scattering. The average particle size and the average PDI of PEG-PLGA nanoparticles were(80.8±0.6) nm, (0.073±0.034). The average drug loading and the average entrapment efficiency were (1.22±0.15) %, (56.10±7.49) % respectively. And the average zeta potential was (-17.90±1.00) mV.
In vitro releasing property of PEG-PLGA nanoparticles was studied and the release of PEG-PLGA nanoparticles was 71.85% for 24 h. TNF-BP releasing from PEG-PLGA nanoparticles in vitro could be described by double phase dynamic model and could be described by the following equation: Q = 0. 008+36.710·(1-e~(-t/0.134))+34.705·(1-e~(-t/2.580)). The in vitro release results showed that the peptide released fast which was probably attributed to the TNF-BP adsorbed to the surface of nanoparticles by electrostatic interactions. The pattern of the fast release may be useful for treatment of acute diseases, such as endotoxic shock and multi-organ function failure.
In vitro uptake of PEG-PLGA nanoparticles by murine peritoneal macrophages (MPM) was analyzed by a flow cytometry. The results indicated that the nanoparticles modified with PEG could reduce the uptake by MPM. Western-blot was used to detect the content of IκB in order to assess the ability of the protection to TNF-BP by the PEG-PLGA nanoparticles. The results showed that PEG-PLGA nanoparticles give high protection to TNF-BP.
(1)研究了载TNF-BP的PLGA长效缓释微球。以TNF-BP为药物,PLGA为载体,通过二次乳化法制备了TNF-BP长效缓释微球,并对所制得的微球进行了表征评价。为了筛选配方的最佳条件,在单因素考察的基础上,通过正交表L16(45)的设计试验,考察了不同因素水平对微球载药量和包封率的影响。采用光学显微镜、扫描电子显微镜、激光散射仪等技术对PLGA微球进行了表征。
对制备的微球采用冷冻干燥技术制备TNF-BP长效缓释微球的冻干粉。通过冷冻干燥工艺的研究,评价了葡萄糖、蔗糖和甘露醇3种多元醇对微球冷冻干燥的影响。
对制备的载药微球进行体外释药研究,并对释药行为进行药物释放数学模型拟合。
(2)研究了载TNF-BP的PEG-PLGA长循环纳米粒。以TNF-BP为药物,PEG-PLGA为载体,通过溶剂挥发法制备具有长循环效能的TNF-BP长循环纳米粒,并对所制得的纳米粒进行了表征评价。为了筛选配方的最佳条件,考察了不同因素对纳米粒粒径及粒径分布的影响。采用透射电子显微镜、激光散射仪等技术对PEG-PLGA纳米粒进行了表征。
对制备的纳米粒进行体外释药研究,并对释药行为进行了药物释放数学模型拟合。
对制备的载药纳米粒进行了初步生物学效应的研究,采用流式细胞仪检测了腹腔巨噬细胞对PEG-PLGA纳米粒的吞噬作用,同时采用Western-blot研究了纳米粒对TNF-BP的保护作用。
通过以上研究获得了以下结果:
(1)通过二次乳化法,采用优化后的工艺制备所得PLGA微球,平均粒径为(10.23±0.03)μm,平均载药量为(13.39±0.29)%,平均药物包封率为(83.54±0.24%)。
(2)冷冻干燥对微球的形态和结构都会产生较大影响,因此必须加入冻干保护剂。在葡萄糖、蔗糖和甘露醇3种多元醇冻干保护剂中,3%的甘露醇具有较好的效果。
(3)TNF-BP微球具有良好的缓释效果,其体外释药行为符合双相动力学模型方程,回归方程为: Q = ?0 .010+38.856·(1-e~(-t/0.496))+27.96·(1-e~(-t/50.004))。
(4)通过溶剂挥发法采用优化后的工艺制备所得PEG-PLGA纳米粒,平均粒径为(80.8±0.6) nm;粒径分布为(0.073±0.034);平均Zeta电位为(-17.90±1.00) mV;平均载药量为(1.22±0.15%);平均药物包封率为(56.10±7.49)%。
(5)PEG-PLGA纳米粒体外释药24 h时,累计释放达到71.85%,表现出TNF-BP纳米粒释放效率极高,对于内毒素性休克引发的急性肺损伤具有极为重要的意义。纳米粒的体外释药符合双相动力学模型方程,回归方程为: Q = 0 .008+36.710·(1-e~(-t/0.134))+34.705·(1-e~(-t/2.580))。
(6)制备的PEG修饰的载药纳米粒能有效避免吞噬,达到长循环的目的,此外,长循环纳米粒对载附的药物TNF-BP具有很高的保护作用。
Tumor Necrosis Factor alpha blocking peptide (TNF-BP), a cycle-seven-peptide, which was shown to be capable to block the biological activities of TNF-α, can protect the joint from inflammol/Latory damage induced by rheumatoid arthritis and reduce the damage from Acute Lung Trauma induced by Endotoxic Shock. The major problem for the application of TNF-BP is that it is a small peptide with molecular weight about 1 kDa so that its half-life time in blood circulation is very short. These often results in low bioavailability. In order to overcome the problems, drug carriers are needed to sustained-release, control delivery and extend half-life of TNF-BP. Two novel drug carriers as sustained-release microspheres and long-circulating nanoparticles would be suitable for our purpose. Poly (lactide-co–glycolic acid) (PLGA), as a biocompatible and slowly degradable polymer, has been targeting, widely used in drug delivery systems, especially in drug-controlled release.
The dissertation consists of two parts. In partⅠ, the subject was to explore the methods of coupling TNF-BP to PLGA microspheres based on double emulsion process, and provide references for the study of targeting, sustained and controlled release delivery systems of TNF-BP. In order to gain the best parameters for preparing PLGA microspheres, the influences of different factors on average drug loading and average entrapment efficiency of PLGA microspheres were evaluated by orthogonal-designing method using L16(45) table. The physicochemical properties of PLGA microspheres were investigated in detail by using optical microscope, scanning electronic microscope (SEM) and laser dynamic scattering. The average particle size of PLGA microspheres was (10.23±0.026)μm. The average drug loading and the average entrapment efficiency were (13.39±0.286)%, (83.54±0.241) % respectively.
The lyophilized powders of TNF-BP-loaded PLGA microspheres were obtained in order to enhance the stability. Glucose, sucrose and mannitol were used as cryoprotectants in the freeze-drying process. Mannitol, concentration in 3%, was selected as the optimum cryoprotectant due to the minimum change of physicochemical properties of PLGA microspheres before and after freeze-drying process.
In vitro releasing property of TNF-BP PLGA microspheres was studied and the drug releasing performance was good. TNF-BP releasing from PLGA microspheres in vitro could be described by double phase dynamic model and could be described by the following equation: Q = ?0. 010+38.856·(1-e~(-t/0.496))+27.96·(1-e~(-t/50.004)).
In partⅡ, the subject was to explore the methods of coupling TNF-BP to polyethyleneglycol-modified poly ( d,l-lactide-co-glycolide ) ( PEG-PLGA ) nanoparticles based on solvent evaporation process, and provide references for the study of targeting, sustained and controlled release delivery systems of TNF-BP. In order to gain the best parameters for preparing PEG-PLGA nanoparticles, the influences of some factors on average particle size and polydispersity index (PDI) of PEG-PLGA nanoparticles such as the type of polymer, the polymer concentration, the type of emulsifiers and the emulsifier concentration were studied. The size, morphology and zeta potential of PEG-PLGA nanoparticles were investigated in detail by using transmission electronic microscope (TEM), Zeta potential analysis and laser dynamic scattering. The average particle size and the average PDI of PEG-PLGA nanoparticles were(80.8±0.6) nm, (0.073±0.034). The average drug loading and the average entrapment efficiency were (1.22±0.15) %, (56.10±7.49) % respectively. And the average zeta potential was (-17.90±1.00) mV.
In vitro releasing property of PEG-PLGA nanoparticles was studied and the release of PEG-PLGA nanoparticles was 71.85% for 24 h. TNF-BP releasing from PEG-PLGA nanoparticles in vitro could be described by double phase dynamic model and could be described by the following equation: Q = 0. 008+36.710·(1-e~(-t/0.134))+34.705·(1-e~(-t/2.580)). The in vitro release results showed that the peptide released fast which was probably attributed to the TNF-BP adsorbed to the surface of nanoparticles by electrostatic interactions. The pattern of the fast release may be useful for treatment of acute diseases, such as endotoxic shock and multi-organ function failure.
In vitro uptake of PEG-PLGA nanoparticles by murine peritoneal macrophages (MPM) was analyzed by a flow cytometry. The results indicated that the nanoparticles modified with PEG could reduce the uptake by MPM. Western-blot was used to detect the content of IκB in order to assess the ability of the protection to TNF-BP by the PEG-PLGA nanoparticles. The results showed that PEG-PLGA nanoparticles give high protection to TNF-BP.
引文
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