南方医科大学学报

南方医科大学学报 ›› 2017, Vol. 37 ›› Issue (07): 975-.

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胰岛素缓释载体聚乙二醇-聚己内酯-聚甲基丙烯酸-N，N-二乙氨基乙酯的制备及评价

吴蕾，朱雯婷，王俊，刘杰，曾庆冰   

  • 出版日期:2017-07-20 发布日期:2017-07-20

Preparation of nanoparticles for sustained insulin release using poly (ethylene glycol) -poly (ε-caprolactone)-poly (N, N-diethylamino-2-ethylmethaerylate)

  • Online:2017-07-20 Published:2017-07-20

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摘要： 目的制备pH敏感聚乙二醇-聚己内酯-聚甲基丙烯酸-N,N-二乙氨基乙酯（mPEG-PCL-PDEAEMA）载胰岛素缓释纳米粒, 考察其体外释放效果和体内降糖活性。方法结合开环聚合反应和原子转移自由基聚合反应合成具有不同疏水链段的 mPEG-PCL-PDEAEMA，用傅里叶红外光谱和核磁共振氢谱表征其结构；采用纳米沉淀技术制备聚合物载胰岛素纳米粒，动态 光散射法测定粒径，透射电子显微镜观察其形态；BCA法测定载药情况，并考察其体外释放行为；建立糖尿病大鼠模型，监测给 药后血糖水平。结果在pH1.2~7.4 时，聚合物纳米粒的粒径随pH 增大而减小。以90% wt 投药比制备mPEG5k-PCL13k- PDEAEMA10k 和mPEG5k-PCL10k-PDEAEMA10k 载胰岛素纳米粒时的包封率和载药率为最佳，包封率分别为（81.99± 1.77）%和（53.12±0.62）%，载药率分别为（42.46±0.53）%和（32.34±0.26）%，粒径分别为181.9±6.67 nm和169±7.1 nm。体外释放 结果显示聚合物载胰岛素纳米粒具有出色的缓释行为，并且随着疏水链段的增长，药物释放速度减慢。体内药效实验表明 mPEG5k-PCL13k-PDEAEMA10k载胰岛素纳米粒能够在体内保持48 h的降血糖效果，较游离胰岛素的降糖作用时间明显延 长。结论pH敏感三嵌段聚合物mPEG-PCL-PDEAEMA有望成为理想的胰岛素缓释载体。

Abstract: Objective To prepare an insulin-loaded nanoparticle assembled using pH-sensitive poly(ethylene glycol)-poly (ε-caprolactone)-poly(N,N-diethylamino-2-ethylmethaerylate) (mPEG-PCL-PDEAEMA) and investigate its performance of sustained insulin release in vitro and its hypoglycemic effects in diabetic rats. Methods mPEG-PCL-PDEAEMA triblock copolymers with different hydrophobic lengths were synthesized by ring opening polymerization (ROP) combined with atom transfer radical polymerization (ATRP). The copolymers were characterized using Fourier-transform Infrared (FT-IR) spectroscopy and proton nuclear magnetic resonance spectroscopy (1H-NMR). Insulin-loaded nanoparticles were prepared by nanoprecipitation technique, in which the reversible swelling of the pH-sensitive material was used for insulin loading and release. The obtained nanoparticles were further confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The entrapment efficiency (EE%), drug loading (DL%) and in vitro release characteristics of the insulinloaded nanoparticles were assessed using BCA protein assay kit. The hypoglycemic effects of the nanoparticles were evaluated by monitoring the glucose levels. Results The size of the nanoparticles decreased as pH value increased within the range of 1.2 to 7.4. Using copolymers mPEG5k-PCL13k- PDEAEMA10k and mPEG5k-PCL10k-PDEAEMA10k as the drug carriers, the nanoparticles prepared with an optimal insulin-coplymer mass ratio of 90% had an average size of 181.9±6.67 nm and 169±7.1 nm, maximal EE% of (81.99±1.77)% and (53.12±0.62)%, and maximal DL% of (42.46±0.53)% and (32.34±0.26)%, respectively. Compared with free insulin, the insulin-loaded nanoparticles was capable of sustained insulin release and the release rate was lowered as the hydrophobic length increases. In diabetic rats, the insulin-loaded nanoparticles based on mPEG5k-PCL13k- PDEAEMA10k maintained a sustained hypoglycemic effect for 48 h, which was significantly longer than the time of free insulin. Conclusion The pH-sensitive triblock copolymer mPEG-PCL-PDEAEMA can serve as a promising candidate of carrier for sustained release of insulin.