寡聚精氨酸促进胰岛素纳米粒肠道吸收

Poly(arginine)8 enhanced intestinal absorption of insulin-loaded nanoparticles

探索一种穿膜肽寡聚精氨酸[poly(arginine)8,R8]修饰的可生物降解乳酸/羟基乙酸共聚物[poly(lactic-co-glycolic acid),PLGA]纳米粒作为胰岛素(insulin,INS)口服给药载体的可行性。采用复乳-溶剂挥发法制备包载胰岛素的PLGA纳米粒(INS-NP),R8经聚乙二醇桥联修饰于该纳米粒表面(R8-INS-NP)。对纳米粒进行理化性状表征及体外释放特性考察,并进行正常大鼠在体灌肠给药的药动学与药效学评价。所得纳米粒平均粒径为(179.0±5.2)nm,多分散系数为0.152±0.042,胰岛素包封率为(29.10±2.59)%,载药量为(5.05±0.50)%,体外释放呈先快后慢的两相模式。给药剂量为10 U.kg—1时,R8-INS-NP的降血糖效果显著优于同剂量的INS-NP,而且D-构型R8修饰的纳米粒(D-R8-INS-NP)吸收优于L-构型R8修饰的纳米粒(L-R8-INS-NP)。与皮下注射相比,INS-NP、L-R8-INS-NP和D-R8-INS-NP在体灌肠给药的相对生物利用度分别为0.52%、4.78%和8.39%,药理相对生物利用度分别为2.07%、3.90%和8.24%。纳米粒表面经R8修饰可促进其包载的胰岛素经肠道吸收,为实现多肽、蛋白类生物大分子口服给药提供了新思路。

The purpose of this study is to investigate the feasibility of poly（arginine）8 （R8） modified poly（lactic-co-glycolic acid） （PLGA） nanoparticles as a cartier for the oral delivery of insulin. Insulin-loaded PLGA nanoparticle （INS-NP） was prepared by a double emulsion-solvent evaporation method, and R8 was subsequently conjugated to the surface of the INS-NP via polyethylene glycol bridge （R8-INS-NP）. The physical and chemical features of the nanoparticles were characterized, and insulin release was determined in vitro. The pharrnacokinetics and pharmacodynamics were evaluated by in situ absorption study with the intestinal loop of rats. The blood glucose level was determined by glucose oxidize method and the serum insulin concentration was determined by radioimmunoassay （RIA）. The mean diameter of INS-NP was （179.0 ± 5.2） nm and the polydispersity index was 0.152 ±0.042, while the entrapment efficiency was （29.10 4±2.59） %. The in vitro release behavior of insulin showed an initial burst effect followed by a stage of slow release. After administrating 10 U.kg-1 insulin to rats, R8-INS-NPs decreased the plasma glucose level much lower than 1NS-NPs, meanwhile, D-form R8 substantially enhanced intestinal absorption of insulin much more than L-form R8. Compared to subcutaneous injection, the relative bioavailabilities of insulin were 0.52%, 4.78%, 8.39%, and the pharmacological bioavailabilities were 2.07%, 3.90%, 8.24%, separately. The R8-modified nanoparticlespromoted the intestinal absorption of insulin, which might be a potential approach for oral delivery of peptide, protein and even other hydrophilic macromolecules in the future.