Zhang Jinjie, Li Jianbo, Ju Yuan, Fu Yao, Gong Tao, Zhang Zhirong
Key Laboratory of Drug Targeting, Ministry of Education, Sichuan University , No. 17. Section 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
Mol Pharm. 2015 Feb 2;12(2):504-13. doi: 10.1021/mp5005806. Epub 2015 Jan 7.
Phospholipid complex (PLC) based self-nanoemulsifying drug delivery system (PLC-SNEDDS) has been developed for efficient delivery of drugs with poor solubility and low permeability. In the present study, a BCS class IV drug and a P-glycoprotein (P-gp) substrate, morin, was selected as the model drug to elucidate the oral absorption mechanism of PLC-SNEDDS. PLC-SNEDDS was superior to PLC in protecting morin from degradation by intestinal enzymes in vitro. In situ perfusion study showed increased intestinal permeability by PLC was duodenum-specific. In contrast, PLC-SNEDDS increased morin permeability in all intestinal segments and induced a change in the main absorption site of morin from colon to ileum. Moreover, ileum conducted the lymphatic transport of PLC-SNEDDS, which was proven by microscopic intestinal visualization of Nile red labeled PLC-SNEDDS and lymph fluids in vivo. Low cytotoxicity and increased Caco-2 cell uptake suggested a safe and efficient delivery of PLC-SNEDDS. The increased membrane fluidity and disrupted actin filaments were closely associated with the increased cell uptake of PLC-SNEDDS. PLC-SNEDDS could be internalized into enterocytes as an intact form in a cholesterol-dependent manner via clathrin-mediated endocytosis and macropinocytosis. The enhanced oral absorption of morin was attributed to the P-gp inhibition by Cremophor RH and the intact internalization of M-PLC-SNEDDS into Caco-2 cells bypassing P-gp recognition. Our findings thus provide new insights into the development of novel nanoemulsions for poorly absorbed drugs.
基于磷脂复合物（PLC）的自纳米乳化药物递送系统（PLC-SNEDDS）已被开发用于高效递送溶解度差和渗透性低的药物。在本研究中，选择一种BCS IV类药物和P-糖蛋白（P-gp）底物桑色素作为模型药物，以阐明PLC-SNEDDS的口服吸收机制。PLC-SNEDDS在体外保护桑色素免受肠道酶降解方面优于PLC。原位灌注研究表明，PLC增加的肠道通透性具有十二指肠特异性。相比之下，PLC-SNEDDS增加了桑色素在所有肠段的通透性，并使桑色素的主要吸收部位从结肠变为回肠。此外，回肠介导了PLC-SNEDDS的淋巴转运，这在体内通过尼罗红标记的PLC-SNEDDS和淋巴液的肠道显微镜观察得到证实。低细胞毒性和Caco-2细胞摄取增加表明PLC-SNEDDS的递送安全有效。膜流动性增加和肌动蛋白丝破坏与PLC-SNEDDS细胞摄取增加密切相关。PLC-SNEDDS可以通过网格蛋白介导的内吞作用和巨胞饮作用以胆固醇依赖性方式完整形式内化到肠细胞中。桑色素口服吸收增强归因于聚氧乙烯蓖麻油RH对P-gp的抑制以及M-PLC-SNEDDS绕过P-gp识别完整内化到Caco-2细胞中。因此，我们的研究结果为开发用于吸收不良药物的新型纳米乳剂提供了新的见解。
