Surface features are key to the transcellular transport of nanoparticles (NPs) across intestinal epithelium cells. Endowing the NPs with specific surface features adapted to the physiological conditions of the gastrointestinal (GI) tract holds great potential for the oral delivery of peptide/protein drugs. Therefore, in this work, a glutamic acid conjugated amphiphilic dendrimer (Glu-APD) was synthesized to replace the widely used 1,2-distearoyl-sn-glycero-3-phosphatidyl-ethanolamine-polyethylene glycol (DSPE-PEG) in the preparation of poly(lactic-co-glycolic acid) (PLGA)-based NPs. Glu-APD could provide the formed NPs (Glu-APD NPs) with specific surface features of dendritic oligopeptides. With such surface features, Glu-APD NPs exhibited a 7.78-fold increase in cellular uptake and a 2.17-fold increase in the transepithelial transport amount compared with those of the DSPE-PEG2000 modified counterparts (P NPs). Instead of a dominant clathrin-mediated endocytosis as shown by P NPs, Glu-APD can provide the NPs with optional endocytosis pathways (i.e. clathrin-mediated, caveolae-mediated and micropinocytosis pathways), with the involvement of oligopeptide transporters and amino acid transporters, subsequently leading to a broadened intracellular trafficking route via the endoplasmic reticulum (ER) and Golgi apparatus. Furthermore, l-glutamic acid (l-Glu), a natural nutrient, could specifically facilitate the exocytosis of Glu-APD NPs, indicating an amino-acid-associated intracellular trafficking. Oral administration of insulin-loaded Glu-APD NPs could also achieve a good hypoglycemic effect with a relative bioavailability of 10.04%, which is 1.89-fold higher than that of P NPs and 5.20-fold higher than insulin solution. Safety evaluations further verified the biocompatibility of Glu-APD NPs and the related materials. The results confirmed the feasibility of introducing Glu-APD to NPs for improving the oral delivery of insulin. With the surface features of dendritic peptide, Glu-APD could facilitate oligopeptide/amino-acid-associated transport of the related NPs, which might be considered as an advantage under physiological conditions. This work might also be considered as a valid reference for the construction of highly efficient oral delivery systems.

中文翻译：

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具有树突状寡肽表面特征的纳米颗粒作为潜在的口服药物递送系统。

表面特征是纳米颗粒（NP）跨肠上皮细胞跨细胞运输的关键。使NP具有适应胃肠道（GI）的生理条件的特定表面特征，对于肽/蛋白质药物的口服递送具有巨大的潜力。因此，在这项工作中，合成了谷氨酸共轭两亲树状聚合物（Glu-APD）来代替制备中广泛使用的1,2-二硬脂酰基-sn-甘油-3-磷脂酰-乙醇胺-聚乙二醇（DSPE-PEG）聚乳酸-乙醇酸（PLGA）基纳米颗粒的制备。Glu-APD可以为形成的NPs（Glu-APD NPs）提供树突状寡肽的特定表面特征。具有这种表面特征的Glu-APD NPs的细胞摄取增加了7.78倍，而Glu-APD NPs则增加了2倍。与DSPE-PEG2000修饰的对应物（P NP）相比，上皮运输量增加了17倍。Glu-APD可以代替NP所显示的占主导地位的网格蛋白介导的内吞作用，而可以为NP提供可选的内吞途径（即网格蛋白介导的，小窝介导的和微胞饮作用的途径），并涉及寡肽转运蛋白和氨基酸转运蛋白，随后导致通过内质网（ER）和高尔基体细胞扩大的细胞内运输途径。此外，天然营养素l-谷氨酸（l-Glu）可以特别促进Glu-APD NP的胞吐作用，这表明氨基酸相关的细胞内运输。口服胰岛素载Glu-APD NPs也可以达到良好的降血糖作用，相对生物利用度为10.04％，比P NPs高1.89倍，比胰岛素溶液高5.20倍。安全性评估进一步验证了Glu-APD NP与相关材料的生物相容性。结果证实了将Glu-APD引入NP改善胰岛素口服递送的可行性。具有树突状肽的表面特征，Glu-APD可以促进相关NP的寡肽/氨基酸相关运输，这在生理条件下可能是一个优势。这项工作也可以被视为构建高效口服给药系统的有效参考。结果证实了将Glu-APD引入NP改善胰岛素口服递送的可行性。具有树突状肽的表面特征，Glu-APD可以促进相关NP的寡肽/氨基酸相关运输，这在生理条件下可能是一个优势。这项工作也可以被视为构建高效口服给药系统的有效参考。结果证实了将Glu-APD引入NP改善胰岛素口服递送的可行性。具有树突状肽的表面特征，Glu-APD可以促进相关NP的寡肽/氨基酸相关运输，这在生理条件下可能是一个优势。这项工作也可以被视为构建高效口服给药系统的有效参考。