Thermosensitive and mucoadhesive poloxamer 407/sodium alginate hydrogel loaded with spermidine for targeted autophagy activation and mucosal repair in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by the superficial mucosa ulcer and inflammation. Spermidine (SPD) has been demonstrated to alleviate the relapse of acute colitis without the systemic immune function compromise via restoring the intestinal mucosal barrier. However, due to its rapid systemic absorption in small intestine and extensive metabolism in liver, the orally administered spermidine had limited access to the diseased colon. Herein, a thermosensitive and mucoadhesive hydrogel (PA) composed of poloxamer 407 and sodium alginate has been developed to rectally deliver SPD for UC treatment. SPD-loaded PA hydrogel (PA-SPD) exhibited the rapid gelation within 1 min at 37 °C, and the adhesive strength of 3.3 × 10³ mN toward fresh colon tissues, both of which ensured its effective retention on the ulcer colon. Moreover, the sustained-release profile of SPD from PA-SPD was presented, with just 23 % of SPD was released at 2 h while more than 80 % was released at 6 h. In DSS-induced colitis mice, PA-SPD significantly reduced disease severity, restored colon length (8.2 cm vs. 5.3 cm in controls), and lowered the level of IL-6, TNF-α, IL-1β. Moreover, PA-SPD treatment could restore gut epithelial barrier integrity via upregulating expression of ZO-1, occludin, claudin-5, and MUC2. The repairing mechanism of PA-SPD was highly associated with activating the Autophagy of gut epithelial to induce stem cell proliferation and differentiation. Collectively, PA might be a promising topical delivery carrier of SPD for ulcerative colitis treatment.

Spermidine; Thermosensitive hydrogel; Ulcerative colitis.