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聚精氨酸纳米胶囊的合理设计旨在帮助肽类克服肠道屏障。

Rational design of polyarginine nanocapsules intended to help peptides overcoming intestinal barriers.

机构信息

Department of Pharmacy and Pharmaceutical Technology, CIMUS Research Institute, IDIS research Institute, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.

ECSIN-European Center for the Sustainable Impact of Nanotechnology, ECAMRICERT SRL, I-45100 Rovigo, Italy.

出版信息

J Control Release. 2017 Oct 10;263:4-17. doi: 10.1016/j.jconrel.2017.02.024. Epub 2017 Feb 21.

Abstract

The aim of this work was to rationally design and characterize nanocapsules (NCs) composed of an oily core and a polyarginine (PARG) shell, intended for oral peptide delivery. The cationic polyaminoacid, PARG, and the oily core components were selected based on their penetration enhancing properties. Insulin was adopted as a model peptide to assess the performance of the NCs. After screening numerous formulation variables, including different oils and surfactants, we defined a composition consisting of oleic acid, sodium deoxycholate (SDC) and Span 80. This selected NCs composition, produced by the solvent displacement technique, exhibited the following key features: (i) an average size of 180nm and a low polydispersity (0.1), (ii) a high insulin association efficacy (80-90% AE), (iii) a good colloidal stability upon incubation in simulated intestinal fluids (SIF, FaSSIF-V2, FeSSIF-V2), and (iv) the capacity to control the release of the associated insulin for >4h. Furthermore, using the Caco-2 model cell line, PARG nanocapsules were able to interact with the enterocytes, and reversibly modify the TEER of the monolayer. Both cell adhesion and membrane permeabilization could account for the pronounced transport of the NCs-associated insulin (3.54%). This improved interaction was also visualized by confocal fluorescent microscopy following oral administration of PARG nanocapsulesto mice. Finally, in vivo efficacy studies performed in normoglycemic rats showed a significant decrease in their plasma glucose levels after treatment. In conclusion, here we disclose key formulation elements for making possible the oral administration of peptides.

摘要

本工作旨在通过合理设计和表征纳米胶囊(NCs),以实现肽类的口服递送。这些 NCs 的内核为油相,外壳由聚精氨酸(PARG)组成。选择阳离子聚氨基酸 PARG 和油性内核成分的依据是它们的渗透增强特性。我们选择胰岛素作为模型肽来评估 NCs 的性能。在筛选了大量制剂变量,包括不同的油相和表面活性剂后,我们确定了由油酸、脱氧胆酸钠(SDC)和司盘 80 组成的配方。通过溶剂置换技术制备的这种选定的 NCs 配方具有以下关键特征:(i)平均粒径为 180nm,多分散性低(0.1),(ii)胰岛素结合效率高(80-90%AE),(iii)在模拟肠液(FaSSIF-V2、FeSSIF-V2)中孵育时具有良好的胶体稳定性,(iv)能够控制相关胰岛素的释放超过 4 小时。此外,使用 Caco-2 模型细胞系,PARG 纳米胶囊能够与肠细胞相互作用,并可逆地改变单层的 TEER。细胞黏附和膜通透性都可以解释 NCs 相关胰岛素(3.54%)的显著转运。口服给予 PARG 纳米胶囊后,通过共聚焦荧光显微镜也可以观察到这种改善的相互作用。最后,在正常血糖大鼠体内药效学研究中,经治疗后其血浆葡萄糖水平显著降低。总之,本研究揭示了实现肽类口服给药的关键制剂要素。

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