Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy , Sichuan University , No. 17, Block 3, Southern Renmin Road , Chengdu 610041 , P.R. China.
Mol Pharm. 2018 Sep 4;15(9):4273-4283. doi: 10.1021/acs.molpharmaceut.8b00713. Epub 2018 Aug 23.
The intestinal epithelium constitutes a major barrier for orally delivered nanoparticles (NPs). Although surface ligand modification can increase cellular uptake of NPs, the transepithelial transport of active targeting NPs is relatively limited. The phenomenon is described as "easy entry, hard transcytosis". However, underlying mechanisms and potential solutions of this phenomenon are unclear. Here, butyrate modified polyethylene glycol coated NPs (Bu-PEG NPs) were chosen as the model active targeting NPs. Transport mechanism studies were performed to get a better understanding of intracellular trafficking and exocytosis fate. Results showed that after active binding to monocarboxylate transporter-1 (MCT-1), Bu-PEG NPs went through endolysosomal pathways, endoplasmic reticulum/Golgi recycling routes, and microtubule-dependent shuttling within Caco-2 cells. Then a larger proportion of Bu-PEG NPs was exocytosed from apical side. Notably, increasing the basal expression of MCT-1 by leptin facilitated basal exocytosis and transcytosis of Bu-PEG NPs, which confirmed that enhanced receptor recognition could promote "basal exit". In addition to the effect of receptor recognition, surface properties also influenced the bidirectional exocytosis of Bu-PEG NPs. When surface hydrophobicity increased, Bu-PEG NPs were dominantly exocytosed from basal membrane. Hence, two strategies may help to overcome "hard transcytosis" of active targeting NPs. One is to enhance their affinity with basal membrane by reinforcing the receptor-ligand interaction; the other is to weaken apical exocytosis by optimizing surface hydrophobicity. Thereby, this study might provide important implications for the rational design of NPs to further increase transepithelial transport efficiency.
肠上皮构成了口服纳米颗粒（NPs）的主要屏障。尽管表面配体修饰可以增加 NPs 的细胞摄取，但主动靶向 NPs 的跨上皮转运仍然相对有限。这种现象被描述为“易入难出”。然而，这种现象的潜在机制和潜在解决方案尚不清楚。在此，选择丁酸修饰的聚乙二醇包覆 NPs（Bu-PEG NPs）作为主动靶向 NPs 的模型。进行转运机制研究以更好地了解细胞内转运和胞吐作用的命运。结果表明，Bu-PEG NPs 与单羧酸转运蛋白-1（MCT-1）主动结合后，通过内溶酶体途径、内质网/高尔基体循环途径以及微管依赖性穿梭在 Caco-2 细胞内转运。然后，更大比例的 Bu-PEG NPs 从顶端侧被胞吐。值得注意的是，瘦素增加 MCT-1 的基础表达促进了 Bu-PEG NPs 的基底胞吐和转胞作用，这证实了增强受体识别可以促进“基底出口”。除了受体识别的影响外，表面性质也影响 Bu-PEG NPs 的双向胞吐作用。当表面疏水性增加时，Bu-PEG NPs 主要从基底膜中被胞吐。因此，两种策略可能有助于克服主动靶向 NPs 的“难转胞”。一种方法是通过增强受体-配体相互作用来增强它们与基底膜的亲和力；另一种是通过优化表面疏水性来减弱顶端胞吐作用。因此，本研究可能为合理设计 NPs 以进一步提高跨上皮转运效率提供重要启示。
