Chylomicrons-Simulating Sustained Drug Release in Mesenteric Lymphatics for the Treatment of Crohn’s-Like Colitis

Abstract

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.

Targeting the Gut Mucosal Immune System Using Nanomaterials

“…These nanomaterials can be packaged into chylomicrons and show an increase in transport through enterocytes compared to free drug or uncoated nanomaterials. Yin et al used a lipid-coated nanoparticle formulation to deliver an immunomodulatory drug, Laquinimod (LAQ), to treat Crohn's disease, an autoimmune disease [90]. They used a mesoporous silica nanoparticles coated with α-α dilaurin to mimic TGs [90].…”

“…Yin et al used a lipid-coated nanoparticle formulation to deliver an immunomodulatory drug, Laquinimod (LAQ), to treat Crohn's disease, an autoimmune disease [90]. They used a mesoporous silica nanoparticles coated with α-α dilaurin to mimic TGs [90]. They also added an acid resistant coating to protect the nanoparticles from gastric fluids that would otherwise lead to their degradation [90].…”

“…They used a mesoporous silica nanoparticles coated with α-α dilaurin to mimic TGs [90]. They also added an acid resistant coating to protect the nanoparticles from gastric fluids that would otherwise lead to their degradation [90]. When the nanoparticle system was delivered orally to mice with Crohn's disease, they found that nanoparticles were transported to the lacteals and the downstream mesenteric lymphatic vessels.…”

“…When the nanoparticle system was delivered orally to mice with Crohn's disease, they found that nanoparticles were transported to the lacteals and the downstream mesenteric lymphatic vessels. The group also explored how their drug delivery system affected lymphangiogenesis, which is commonly associated with Crohn's disease and is thought to be a way to compensate for dysfunctional mesenteric lymphatic vessels [90]. Lymphangiogenesis is mediated by the binding of growth factors VEGF-C and VEGF-D to VEGFR3, and the researchers found that their formulation caused a significant decrease in VEGF-C and VEGFR3 expression compared to control groups.…”

Role of mesenteric component in Crohn’s disease: A friend or foe?

“…These studies suggest that mesenteric lymphatics may be a promising potential target for CD treatment. Recently, we found that intestinal inflammation was significantly improved by the application of lymphatics-targeting drug release in the IL-10 -/- spontaneous experimental colitis, suggesting that mesenteric LVs are potential targets for CD treatment[ 80 ].…”