Abstract：
Local drug delivery to the esophagus is hampered by rapid transit time and poor permeability of the mucosa. If some strategies aimed to improve the residence time have been proposed, non-invasive approaches to increase the drug penetration in the mucosa have not been described so far. Herein, we designed mucosa-penetrating liposomes to favor the penetration and retention of curcumin (CURC) in the esophagus. A novel mucosa penetrating peptide (MPP), SLENKGP, was selected by Phage Display and conjugated to pegylated liposomes at different PEG and MPP\'s surface densities. Pegylation assured a long residence time of liposomes (at least 30 min) in the esophagus in vivo, but it did not favor the penetration of CURC in the mucosa. MPP-decorated liposomes instead delivered a significant higher amount of CURC in the mucosa compared to naked pegylated liposomes. Confocal microscopy studies showed that naked pegylated liposomes remain confined in the superficial layers of the mucosa whereas MPP-decorated liposomes penetrate the whole epithelium. In vitro, MPP reduced the interaction of PEG with mucin, meanwhile favoring the paracellular penetration of liposomes across epithelial cell multilayers. In conclusion, pegylated liposomes represent a valid approach to target the esophagus and the surface functionalization with MPP enhances their penetration in the mucosa.
摘要：
向食道的局部药物递送受到快速运输时间和粘膜渗透性差的阻碍。如果提出了一些旨在改善停留时间的策略，到目前为止，尚未描述增加药物在粘膜中渗透的非侵入性方法。在这里，我们设计了粘膜穿透性脂质体,以促进姜黄素(CURC)在食管中的渗透和滞留.一种新的粘膜穿透肽（MPP），SLENKGP,通过噬菌体展示选择，并以不同的PEG和MPP表面密度与聚乙二醇化脂质体缀合。聚乙二醇化确保脂质体在体内食道中的长停留时间（至少30分钟），但它不利于CURC在粘膜中的渗透。与裸露的聚乙二醇化脂质体相比，MPP修饰的脂质体在粘膜中递送了显着更高量的CURC。共聚焦显微镜研究表明，裸露的聚乙二醇化脂质体仍局限于粘膜的表层，而MPP修饰的脂质体则穿透整个上皮。体外，MPP降低了PEG与粘蛋白的相互作用，同时有利于脂质体通过上皮细胞多层膜的细胞旁渗透。总之,聚乙二醇化脂质体代表了靶向食道的有效方法，并且MPP的表面功能化增强了它们在粘膜中的渗透。
