Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery
Dual-modified nanoparticles overcome sequential absorption barriers for oral insulin delivery
复制标题
双修饰纳米颗粒克服了口服胰岛素输送的连续吸收障碍
DOI：
10.1016/j.jconrel.2021.11.045
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发表时间：
2021
影响因子：
10.8
通讯作者：
Yong Gan
中科院分区：
文献类型：
--
作者：
Ziyue Xi;Ejaj Ahmad;Wei Zhang;Aohua Wang;Faridoon;Ning Wang;Chunliu Zhu;Wei Huang;Lu Xu;Miaorong Yu;Yong Gan
口服胰岛素给药的有效性受到多种胃肠道屏障的严重阻碍，尤其是跨上皮屏障，包括顶端内吞、溶酶体降解、胞质扩散和基底外侧胞吐。在这项研究中，一个功能性纳米粒子（PG-FAPEP）与双重修饰的构建顺序解决这些重要的吸收障碍，改善口服胰岛素输送。叶酸和电荷转换三肽的双重表面修饰赋予PG-FAPEP分别靶向肠上皮细胞顶侧和基底侧的能力。PG-FAPEP在粘液层中快速扩散后，可通过叶酸受体介导的途径被有效地内化到上皮细胞中，并在酸性溶酶体中因表面三肽而带正电荷，引发质子海绵效应，从而逃逸溶酶体。当进入胞质介质时，PG-FAPEP再次转化为中性电荷，减弱细胞内粘附，并获得朝向基底外侧的改善的运动性。最后，三肽帮助PG-FAPEP识别基底外侧膜中的质子偶联寡肽转运蛋白（PHT 1），促进整个肠上皮细胞的完整胞吐作用。体内研究进一步证实PG-FAPEP可通过叶酸受体介导的内吞、溶酶体逃逸和PHT 1介导的胞吐作用穿越肠上皮细胞，表现出较高的口服胰岛素生物利用度（14.3%）和延长的降血糖作用。该配方以简单的双重修改策略按需解决多种吸收障碍。因此，这些特征允许PG-FAPEP释放口服大分子递送的潜力。
The efficacy of oral insulin drug delivery is seriously hampered by multiple gastrointestinal barriers, especially transepithelial barriers, including apical endocytosis, lysosomal degradation, cytosolic diffusion and basolateral exocytosis. In this study, a functional nanoparticle (PG-FAPEP) with dual-modification was constructed to sequentially address these important absorption obstacles for improved oral insulin delivery. The dual surface decorations folate and charge-convertible tripeptide endowed PG-FAPEP with the ability to target the apical and basolateral sides of enterocytes, respectively. After fast diffusion across the mucus layer, PG-FAPEP could be efficiently internalized into epithelial cellsviaa folate receptor-mediated pathway and subsequently became positively charged in acidic lysosomes due to the surface tripeptide, triggering the proton sponge effect to escape lysosomes. When entering the cytosolic medium, PG-FAPEP was converted to neutral charge again, attenuating intracellular adhesion, and gained improved motility toward the basolateral side. Finally, the tripeptide helped PG-FAPEP recognize the proton-coupled oligopeptide transporter (PHT1) in the basolateral membrane, boosting intact exocytosis across intestinal epithelial cells. Thein vivostudies further verified that PG-FAPEP could traverse the intestinal epithelium by folate receptor-mediated endocytosis, lysosomal escape, and PHT1-mediated exocytosis, exhibiting a high oral insulin bioavailability of 14.3% and a prolonged hypoglycemic effect. This formulation addresses multiple absorption barriers on demand with a simple dual-modification strategy. Therefore, these features allow PG-FAPEP to unleash the potential of oral macromolecule delivery.