Chylomicrons-simulating sustained drug release in mesenteric lymphatics for the treatment of Crohn's-like colitis
Chylomicrons-simulating sustained drug release in mesenteric lymphatics for the treatment of Crohn's-like colitis
复制标题
乳糜微粒模拟肠系膜淋巴管中的持续药物释放，用于治疗克罗恩病样结肠炎。
DOI：
10.1093/ecco-jcc/jjaa200
复制
发表时间：
2020
影响因子：
8
通讯作者：
Li Y.
中科院分区：
文献类型：
--
作者：
Yin Y;Yang J;Pan Y;Guo Z;Gao Y;Huang L;Zhou D;Ge Y;Guo F;Zhu W;Song Y;Li Y.
背景和目标
肠系膜淋巴管结构和功能的改变是克罗恩病的典型特征。在克罗恩病 [CD] 和实验性结肠炎患者中都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送系统，可以增强肠系膜淋巴组织[MLT]的药物递送并评估克罗恩氏结肠炎的治疗效果。
方法
我们设计了一种与长链脂肪酸[LMSN]缀合的介孔二氧化硅纳米颗粒[MSN]，并覆盖有肠溶衣[ELMSN]，可以通过肠系膜淋巴系统特异性运输。在成熟的 IL-10 -/- 自发性实验性结肠炎中评估了负载拉喹莫德的纳米颗粒的治疗效果。
结果
ELMSN 诱导可持续药物释放，显着增加 MLT 中的药物浓度。在实验性结肠炎中，淋巴靶向给药系统抑制淋巴管炎并促进淋巴引流。促炎细胞因子和下游 NF-κB 相关蛋白的下调有效抑制淋巴管生成并恢复肠系膜淋巴管 [MLV] 的紧密连接。 LAQ@ELMSN 在改善肠道炎症方面表现出优于免费给药的治疗效果。 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。
结论
我们的研究展示了一种方便的口服给药系统，可以增强 MLT 中的药物释放。这些结果证实了肠系膜淋巴系统对肠道炎症发病机制的贡献，并揭示了淋巴靶向药物递送疗法作为 CD 治疗的潜在治疗策略的应用。
BACKGROUND AND AIMS
Alteration of both structures and functions of mesenteric lymphatic vessels is a typical hallmark of Crohn's disease. Dysfunctional lymphatics was observed both in patients with Crohn's disease [CD] and experimental colitis, suggesting mesenteric lymphatics could be potential therapeutic targets. This study was aimed to develop a nano-delivery system which can enhance drug delivery in mesenteric lymphatic tissues [MLT] and evaluate the therapeutic effects in Crohn's colitis.
METHODS
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 mesenteric lymphatic system. The therapeutic efficacy of laquinimod-loaded nanoparticles was evaluated in the well-established IL-10 -/- spontaneous experimental colitis.
RESULTS
ELMSN induced sustainable drug release 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 junction of mesenteric lymphatic vessels [MLVs]. LAQ@ELMSN demonstrated superior therapeutic effect on ameliorating intestinal inflammation over free drug administration. Alteration of gut microbiota and metabolites in experimental colitis was also reversed by LAQ@ELMSN.
CONCLUSION
Our study demonstrates a convenient, oral-administered drug delivery system which enhances drug release in MLT. The results confirm the contribution of 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.