The intestine epithelium is considered to be the most critical obstacle for nanoparticles for oral delivery of water-insoluble and poorly absorbed drugs. Based on the specific transporters located on the apical membrane of the intestinal epithelium, the carnitine-conjugated polymeric micelles targeting to the carnitine/organic cation transporter 2 (OCTN2) were developed by combining carnitine-conjugated poly(2-ethyl-2-oxazoline)-poly(d,l-lactide) with monomethoxy poly(ethylene-glycol)-poly(d,l-lactide). The carnitine-conjugated micelles with favorable stability in gastrointestinal fluid were validated to remarkably increase the cellular internalization and transcellular transport, while these were not the cases in the presence of free carnitine. These were further confirmed by more distribution of the micelles within epithelial cells, on the apical and basolateral side of the epithelium in mice. Additionally, identification of the carnitine-conjugated micelles by OCTN2 was detected to facilitate cellular uptake of the micelles via fluorescence immunoassay. Both clathrin and caveolae/lipid rafts pathways mediated endocytosis and transcellular transport of the carnitine-conjugated micelles, implying the enrichment of endocytic and transcellular transport pathway compared with that of carnitine-unconjugated micelles. Further, the intracellular trafficking process of the carnitine-conjugated micelles was tracked under confocal laser scanning microscopy, which involved in intracellular compartments such as late endosomes, lysosomes, endoplasmic reticulum, and Golgi apparatus as well. In conclusion, the current study provided an efficient strategy to facilitate the oral absorption of water-insoluble and poorly absorbed agents using intestinal transporter-mediated polymeric micelles.

中文翻译：

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使用肉碱/有机阳离子转运蛋白2介导的聚合物胶束有效地将水溶性差的药物有效口服

肠上皮被认为是纳米颗粒口服给药水不溶和吸收不良的药物的最关键障碍。基于位于肠上皮顶膜上的特定转运蛋白，通过结合肉碱结合的聚（2-乙基-2-恶唑啉），开发了针对肉碱/有机阳离子转运蛋白2（OCTN2）的肉碱结合聚合物胶束。 -聚（d，l-丙交酯）与单甲氧基聚（乙二醇）-poly （d，l-丙交酯）。经验证，在胃肠道液中具有良好稳定性的肉碱共轭胶束可显着增加细胞内在化和跨细胞转运，而游离肉碱则并非如此。通过胶束在小鼠上皮的顶侧和基底外侧的上皮细胞内更多的分布进一步证实了这些。此外，检测到通过OCTN2识别肉碱结合的胶束，以促进细胞通过胶束摄取胶束。荧光免疫测定。网格蛋白和小窝/脂质筏途径均介导了肉碱缀合的胶束的内吞作用和跨细胞运输，这意味着与肉碱缀合的胶束相比，内吞和跨细胞运输途径的富集。此外，在共聚焦激光扫描显微镜下跟踪了肉碱缀合的胶束的细胞内运输过程，该显微镜涉及细胞内区室，如晚期内体，溶酶体，内质网和高尔基体。总之，当前的研究提供了一种有效的策略，以促进通过肠转运蛋白介导的聚合物胶束对水不溶性和吸收性差的药物的口服吸收。