Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, School of Pharmaceutical Sciences, Peking University, Beijing 1001 91, China.
ACS Biomater Sci Eng. 2020 Apr 13;6(4):2146-2158. doi: 10.1021/acsbiomaterials.0c00020. Epub 2020 Apr 1.
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 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.
肠上皮被认为是纳米颗粒经口服递送给水不溶性和吸收不良的药物的最关键障碍。基于位于肠上皮细胞顶膜上的特定转运体，通过将肉碱缀合的聚（2-乙基-2-恶唑啉）-聚（d,l-丙交酯）与单甲氧基聚（乙二醇）-聚（d,l-丙交酯）结合，开发了靶向肉碱/有机阳离子转运体 2（OCTN2）的肉碱缀合聚合物胶束。在胃肠道液中具有良好稳定性的肉碱缀合胶束被证实可显著增加细胞内化和跨细胞转运，而在存在游离肉碱的情况下则不是这种情况。这在小鼠中通过胶束在上皮细胞内、上皮细胞的顶端和基底外侧更广泛的分布得到进一步证实。此外，通过荧光免疫测定法检测到 OCTN2 识别肉碱缀合胶束，以促进胶束的细胞摄取。网格蛋白和 caveolae/脂筏途径介导肉碱缀合胶束的内吞作用和跨细胞转运，这意味着与未缀合肉碱的胶束相比，内吞作用和跨细胞转运途径得到了富集。此外，通过共聚焦激光扫描显微镜跟踪肉碱缀合胶束的细胞内转运过程，涉及细胞内隔室，如晚期内体、溶酶体、内质网和高尔基体。总之，本研究提供了一种有效的策略，通过肠转运体介导的聚合物胶束促进水不溶性和吸收不良药物的口服吸收。
