Oral insulin delivery, the challenge to increase insulin bioavailability: Influence of surface charge in nanoparticle system
Oral insulin delivery, the challenge to increase insulin bioavailability: Influence of surface charge in nanoparticle system
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DOI：
10.1016/j.ijpharm.2018.02.045
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发表时间：
2018-05-05
影响因子：
5.8
通讯作者：
Sigrist, Severine
中科院分区：
文献类型：
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作者：
Czuba, Elodie;Diop, Mouhamadou;Sigrist, Severine
口服胰岛素增加了患者的舒适度，并可以改善血糖控制，这要归功于肝脏的第一次通过。然而，挑战依然存在。目前的方法使用了聚(D，乳酸-乙醇酸共聚)纳米粒(NPs)，这是一种有效的药物载体系统，具有长效作用。然而，该系统提供的胰岛素胶囊的生物利用度低于20%。在这种情况下，表面电荷等物理化学参数可能在肠道屏障摄取NP方面发挥关键作用。因此，我们开发了一种简单的方法来调节NP表面电荷，以测试其在体外对摄取的影响，最终对NP在体内的效率的影响。在有(+)或无(-)聚乙烯醇(PVA)、十二烷基硫酸钠(SDS)和/或壳聚糖氯化物包覆的情况下，制备了各种纳米颗粒。用Caco-2上皮细胞培养和Caco-2/RevHT29MTX共培养，用流式细胞仪检测细胞的体外内化。然后用药物复合载体(100或250 uI/kg)口服给药，SDS-NPs(-42+/-2 mV)比-PVA-NPs(-22+/-1 mV)带负电荷，壳聚糖包被的NPs带正电荷(56+/-2 mV)，而+PVA颗粒(-2+/-1 mV)是不带电荷的。在Caco-2模型中，与使用经典NPs(+PVA NPs)和壳聚糖包覆NPs相比，使用负电荷NPs(SDS NPs)显著改善了NP的内化。最后，在体内证明了胰岛素十二烷基硫酸钠纳米粒(100或250 uI胰岛素/kg)对糖尿病大鼠的降糖作用。负电荷NPs的制备是提高NP摄取和胰岛素口服生物利用度的一种很有前途的方法。
Oral administration of insulin increases patient comfort and could improve glycemic control thanks to the hepatic first passage. However, challenges remain. The current approach uses poly (D, lactic-co-glycolic) acid (PLGA) nanoparticles (NPs), an effective drug carrier system with a long acting profile. However, this system presents a bioavailability of less than 20% for insulin encapsulation. In this context, physico-chemical parameters like surface charge could play a critical role in NP uptake by the intestinal barrier. Therefore, we developed a simple method to modulate NP surface charge to test its impact on uptake in vitro and finally on NP efficiency in vivo. Various NPs were prepared in the presence (+) or absence (-) of polyvinyl alcohol (PVA), sodium dodecyl sulfate (SDS), and/or coated with chitosan chloride. In vitro internalization was tested using epithelial culture of Caco-2 or using a co-culture (Caco-2/RevHT29MTX) by flow cytometry. NPs were then administered by oral route using a pharmaceutical complex vector (100 or 250 UI/kg) in a diabetic rat model.SDS-NPs (-42 +/- 2 mV) were more negatively charged than -PVA-NPs (-22 +/- 1 mV) and chitosan-coated NPs were highly positively charged (56 +/- 2 mV) compared to + PVA particles (-2 +/- 1 mV), which were uncharged. In the Caco-2 model, NP internalization was significantly improved by using negatively charged NPs (SDS NPs) compared to using classical NPs (+ PVA NPs) and chitosan-coated NPs. Finally, the efficacy of insulin SDS-NPs was demonstrated in vivo (100 or 250 UI insulin/kg) with a reduction of blood glucose levels in diabetic rats. Formulation of negatively charged NPs represents a promising approach to improve NP uptake and insulin bioavailability for oral delivery.