Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
College of Engineering and Applied Sciences and Jiangsu Key Laboratory of Artificial Functional Materials, State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China.
J Crohns Colitis. 2021 Apr 6;15(4):631-646. doi: 10.1093/ecco-jcc/jjaa200.
Alteration to both the structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn's disease [CD]. Dysfunctional lymphatics was observed in patients with both CD and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissue [MLT] and evaluate the therapeutic effects in Crohn's colitis.
We designed a mesoporous silica nanoparticle [MSN] conjugated with long-chain fatty acid [LMSN] and covered with enteric coating [ELMSN] which can be specifically transported via the mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles [LAQ@ELMSN] was evaluated in the well-established interleukin [IL]-10-/- spontaneous experimental colitis.
ELMSNs induced sustainable drug release that markedly increased drug concentration in MLT. In experimental colitis, the lymphatics-targeting drug delivery system suppressed lymphangitis and promoted lymphatic drainage. The downregulation of pro-inflammatory cytokines and the downstream NF-κB-related proteins efficiently inhibited lymphangiogenesis and restored tight junctions of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN showed a superior therapeutic effect in ameliorating intestinal inflammation compared with free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN.
Our study demonstrates a convenient, orally administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of the mesenteric lymphatic system to the pathogenesis of gut inflammation and shed light on the application of lymphatics-targeting drug delivery therapy as a potential therapeutic strategy for CD treatment.
肠系膜淋巴管的结构和功能改变是克罗恩病[CD]的典型特征。在 CD 和实验性结肠炎患者中均观察到功能失调的淋巴管，这表明肠系膜淋巴管可能是潜在的治疗靶点。本研究旨在开发一种纳米递药系统，该系统可以增强药物在肠系膜淋巴组织[MLT]中的传递，并评估其在克罗恩病结肠炎中的治疗效果。
我们设计了一种长链脂肪酸[LMSN]偶联的介孔硅纳米粒子[MSN]，并覆盖有肠溶性涂层[ELMSN]，可以通过肠系膜淋巴管系统进行特异性运输。我们在已建立的白细胞介素[IL]-10-/-自发性实验性结肠炎中评估了拉喹莫德载药纳米粒[LAQ@ELMSN]的治疗效果。
ELMSNs 诱导了持续的药物释放，显著增加了 MLT 中的药物浓度。在实验性结肠炎中，这种靶向淋巴管的药物传递系统抑制了淋巴管炎并促进了淋巴引流。下调促炎细胞因子和下游 NF-κB 相关蛋白有效地抑制了淋巴管生成并恢复了肠系膜淋巴管[MLVs]的紧密连接。与游离药物给药相比，LAQ@ELMSN 在改善肠道炎症方面显示出更好的治疗效果。LAQ@ELMSN 还逆转了实验性结肠炎中肠道微生物群和代谢物的改变。
本研究证明了一种方便的、口服给药的药物传递系统，该系统可增强 MLT 中的药物释放。研究结果证实了肠系膜淋巴管系统对肠道炎症发病机制的贡献，并为靶向淋巴管的药物传递治疗作为 CD 治疗的一种潜在治疗策略提供了启示。
