Zhou Jie, Li Tian-Le, Wei Bo, Ruan Yue-Feng, Wang Ye-Qin, Liu Jiao-Yan, Song Meng-Meng, Shen Yu-Xian
School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, 230032 Hefei, Anhui, PR China.
Anhui Provincial Institute of Translational Medicine, 230032 Hefei, Anhui, PR China.
Int J Pharm X. 2025 Feb 26;9:100320. doi: 10.1016/j.ijpx.2025.100320. eCollection 2025 Jun.
Midbrain astrocyte-derived neurotrophic factor (MANF) is a secreted protein induced by endoplasmic reticulum stress. Previous studies have indicated that intravenous administration of 1 mg/kg/day recombinant human MANF protein with His tag (His-MANF) for 3 days can ameliorate acute ulcerative colitis in mice. However, long-term intravenous therapy has many disadvantages. In this paper, His-MANF protein was successfully encapsulated into alginate and hyaluronic acid hybrid hydrogel microcapsules in one step using the gas shear method and then coated by Eudragit S100 to construct an oral colon-targeted delivery system (MSH@E). The MSH@E microcapsules exhibited controlled and sustained release behavior and colon-targeting properties. Both fluorescent imaging and immunohistochemistry staining results showed that His-MANF protein could accumulate in the colitis colon for a longer residence time after oral delivery. In vivo studies demonstrated that oral administration of MSH@E microcapsules could alleviate DSS-induced colitis in mice without systemic toxicity. Importantly, even if the oral His-MANF dose was half of the intravenous His-MANF dose, oral delivery was still much more effective than intravenous injection, suggesting the development of the oral colon-targeted delivery system (MSH@E) has great significance and makes a breakthrough from intravenous to oral administration for His-MANF treatment of ulcerative colitis (UC).
中脑星形胶质细胞衍生的神经营养因子（MANF）是一种由内质网应激诱导分泌的蛋白质。先前的研究表明，以1毫克/千克/天的剂量静脉注射带His标签的重组人MANF蛋白（His-MANF），连续注射3天，可改善小鼠的急性溃疡性结肠炎。然而，长期静脉治疗存在诸多弊端。在本文中，采用气体剪切法将His-MANF蛋白一步成功包封于海藻酸钠和透明质酸混合水凝胶微囊中，然后用Eudragit S100进行包衣，构建了口服结肠靶向递送系统（MSH@E）。MSH@E微囊表现出控释和缓释行为以及结肠靶向特性。荧光成像和免疫组化染色结果均表明，口服给药后His-MANF蛋白可在结肠炎结肠中蓄积更长时间。体内研究表明，口服MSH@E微囊可减轻小鼠由葡聚糖硫酸钠（DSS）诱导的结肠炎，且无全身毒性。重要的是，即使口服His-MANF的剂量仅为静脉注射His-MANF剂量的一半，口服给药仍比静脉注射有效得多，这表明口服结肠靶向递送系统（MSH@E）的开发具有重要意义，并且在His-MANF治疗溃疡性结肠炎（UC）方面实现了从静脉给药到口服给药的突破。
