Smart Responsive Quercetin-Conjugated Glycol Chitosan Prodrug Micelles for Treatment of Inflammatory Bowel Diseases

Abstract

The incidence and progression of inflammatory bowel disease are closely related to oxidative stress caused by excessive production of reactive oxygen species (ROS). To develop an efficacious and safe nanotherapy against inflammatory bowel diseases (IBD), we designed a novel pH/ROS dual-responsive prodrug micelle GC-B-Que as an inflammatory-targeted drug, which was comprised by active quercetin (Que) covalently linked to biocompatible glycol chitosan (GC) by aryl boronic ester as a responsive linker. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. Time-dependent NMR spectra traced the changes in the polymer structure in the presence of H 2 O 2 , confirming the release of the drug. The in vitro drug release studies indicated a low release rate (<20 wt %) in physiological conditions, but nearly complete release (>95 wt % after 72 h incubation) in a pH 5.8 medium containing 10 μM H 2 O 2 , exhibiting a pH/ROS dualresponsive property and sustained release behavior. Importantly, the negligible drug release in a simulated gastric environment in 1 h allowed us to perform intragastric administration, which has potential to achieve the oral delivery by mature enteric-coating modification in future. Further in vivo activities and biodistribution experiments found that the GC-B-Que micelles tended to accumulate in intestinal inflammation sites and showed better therapeutic efficacy than the free drugs (quercetin and mesalazine) in a colitis mice model. Typical inflammatory cytokines including TNF-α, IL-6, and iNOS were significantly suppressed by GC-B-Que micelle treatment. Our work promoted inflammatory-targeted delivery and intestinal drug accumulation for active single drug quercetin and improved the therapeutic effect of IBD. The current study also provided an alternative strategy for designing a smart responsive nanocarrier for a catechol-based drug to better achieve the target drug delivery.

Advances in the treatment of inflammatory bowel disease: Focus on polysaccharide nanoparticulate drug delivery systems

“…Low encapsulation efficiency and premature drug release were tackled through the covalent linkage of the drug to the polysaccharide. [331][332][333][334] Compared with physical encapsulation, the prodrug strategy was explored for developing smartresponsive drug-polysaccharides conjugates. 331 In these systems, the drug was released under stimulus (e.g., pH, ROS, enzymes) for specific drug delivery at the site of inflammation.…”

Potential Implications of Quercetin in Autoimmune Diseases

“…Shen et al. ( 69 ) designed a dual-responsive prodrug micelle consisting of quercetin and the biocompatible glycol chitosan, which tended to accumulate in sites of intestinal inflammation, and exhibited better therapeutic efficacy than the free drugs quercetin and mesalazine in a mouse colitis model.…”

Biological Activities Underlying the Therapeutic Effect of Quercetin on Inflammatory Bowel Disease

“…Moreover, heterospheroid (HS) mixture consisting of mesenchymal stem cells (MSCs) and quercetin could maximize the inflammation resolving and tissue reparative capacity as well as the engraftment efficiency of cotransplanted MSCs in colitic mice [ 33 ]. Quercetin conjugated glycol chitosan prodrug micelles or quercetin-loaded nutriose-coated vesicles are both valuable tools for the optimal treatment of IBD [ 49 , 50 ]. Besides, combined quercitrin and dietary oil (rich in n-3 polyunsaturated fatty acids) exhibit synergistic effect on intestinal inflammatory remission in DSS-induced colitis model [ 51 ].…”