Department of Pharmacy, Songjiang Hospital Affiliated Shanghai First People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Urology Department, First Affiliated Hospital of Gannan Medical University, Gannan Medical University, Ganzhou, China.
Sci Rep. 2017 Jan 23;7:41322. doi: 10.1038/srep41322.
It remains a significant challenge to overcome the poor permeability of cyclosporine A and enhance its oral absorption. In this study, we have identified a positively charged chitosan that is able to induce coiling up of anionic lipids to form nanocochleates with an average size of 114.2 ± 0.8 nm, without the need for calcium ions. These functional chitosan-induced nanocochleates enhanced gastrointestinal absorption of cyclosporine A, up to a 3-fold increase in oral bioavailability. A fluorescence-labeling study confirmed that absorption mainly occurred in the duodenum and jejunum. Transport studies indicated that uptake of chitosan-induced nanocochleates by Caco-2 cells was by clathrin- and caveolae-mediated endocytosis, but not by macropinocytosis. Furthermore, three cellular tight junction proteins, ZO-1, F-actin and claudin-4, were significantly down-regulated, suggesting that chitobiose-induced nanocochleates are able to reconstruct and open tight junctions in intestinal epithelial cells to enhance drug absorption. In summary, these novel bifunctional chitosan-induced nanocochleates appear to have potential to facilitate oral delivery of cyclosporine A.
克服环孢素 A 渗透性差并提高其口服吸收仍然是一个重大挑战。在本研究中，我们已经鉴定出一种带正电荷的壳聚糖，它能够诱导阴离子脂质卷曲形成纳米 Cochleates，平均粒径为 114.2 ± 0.8nm，无需钙离子。这些功能性壳聚糖诱导的纳米 Cochleates 增强了环孢素 A 的胃肠道吸收，口服生物利用度提高了 3 倍。荧光标记研究证实，吸收主要发生在十二指肠和空肠。转运研究表明，Caco-2 细胞对壳聚糖诱导的纳米 Cochleates 的摄取是通过网格蛋白和小窝蛋白介导的内吞作用，但不是通过巨胞饮作用。此外，三种细胞紧密连接蛋白 ZO-1、F-肌动蛋白和 Claudin-4 显著下调，表明壳二糖诱导的纳米 Cochleates 能够重建和打开肠上皮细胞中的紧密连接，从而增强药物吸收。总之，这些新型双功能壳聚糖诱导的纳米 Cochleates 似乎有可能促进环孢素 A 的口服递送。
