Fang Guihua, Tang Bo, Chao Yanhui, Xu Helin, Gou Jingxin, Zhang Yu, Xu Hui, Tang Xing
School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, China.
Mol Pharm. 2015 Jul 6;12(7):2384-95. doi: 10.1021/acs.molpharmaceut.5b00081. Epub 2015 May 28.
Here we report the development and evaluation of cysteine-modified nanostructured lipid carriers (NLCs) for oral delivery of docetaxel (DTX). The NLCs ensure high encapsulation efficiency of docetaxel, while the cysteine bound the NLCs with PEG2000-monostearate (PEG2000-MSA) as a linker, and allowed a specific interaction with mucin of the intestinal mucus layer and facilitated the intestinal transport of docetaxel. The cysteine-modified NLCs (cNLCs) had a small particle size (<100 nm) and a negative zeta potential (-13.72 ± 0.07 mV), which was lower than that of the unmodified NLCs (uNLCs) (-6.39 ± 0.07 mV). This correlates well with the location of the cysteine group on the surface of the NLCs obtained by X-ray photoelectron spectroscopy (XPS). The cNLCs significantly improved the mucoadhesion properties compared with uNLCs. The intestinal absorption of cNLCs in total intestinal segments was greatly improved in comparison with uNLCs and docetaxel solution (DTX-Sol), and the in vivo imaging system captured pictures also showed not only increased intestinal absorption but also improved accumulation in blood. The cNLCs could be absorbed into the enterocytes via both endocytosis and passive transport. The results of the in vivo pharmacokinetic study indicated that the AUC0-t of cNLCs (1533.00 ng/mL·h) was markedly increased 12.3-fold, and 1.64-fold compared with docetaxel solution and uNLCs, respectively. Overall, the cysteine modification makes nanostructured lipid carriers more suitable as nanocarriers for oral delivery of docetaxel.
在此，我们报告了用于多西他赛（DTX）口服给药的半胱氨酸修饰的纳米结构脂质载体（NLCs）的研发与评估。NLCs确保了多西他赛的高包封率，而半胱氨酸以聚乙二醇2000 - 单硬脂酸酯（PEG2000 - MSA）作为连接剂与NLCs结合，并允许与肠黏液层的黏蛋白发生特异性相互作用，促进了多西他赛的肠道转运。半胱氨酸修饰的NLCs（cNLCs）具有小粒径（<100 nm）和负的zeta电位（-13.72±0.07 mV），低于未修饰的NLCs（uNLCs）（-6.39±0.07 mV）。这与通过X射线光电子能谱（XPS）获得的NLCs表面半胱氨酸基团的位置密切相关。与uNLCs相比，cNLCs显著改善了黏膜黏附性能。与uNLCs和多西他赛溶液（DTX - Sol）相比，cNLCs在整个肠段的肠道吸收有了极大改善，体内成像系统拍摄的图片也显示不仅肠道吸收增加，而且血液中的蓄积也有所改善。cNLCs可通过内吞作用和被动转运被吸收进入肠上皮细胞。体内药代动力学研究结果表明，cNLCs的AUC0 - t（1533.00 ng/mL·h）分别比多西他赛溶液和uNLCs显著增加了12.3倍和1.64倍。总体而言，半胱氨酸修饰使纳米结构脂质载体更适合作为多西他赛口服给药的纳米载体。
