Shujie Cheng1, Haowen Shen2, Sibo Zhao3, Yuanxin Zhang1, Hui Xu1, Lancheng Wang3, Bin Di4, Lili Xu4, Chi Hu3. 1. Department of Food Quality and Safety, School of Engineering, China Pharmaceutical University, Nanjing 210009, PR China and National R&D Center for Chinese Herbal Medicine Processing, China Pharmaceutical University, Nanjing 210009, PR China. 2. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing 210009, PR China. dibin@cpu.edu.cn 1620174420@cpu.edu.cn and Jiangsu Institute of Medical Device Testing, Nanjing 210019, PR China. 3. Department of Pharmaceutical Engineering, School of Engineering, China Pharmaceutical University, Nanjing 211198, PR China. chihu@cpu.edu.cn. 4. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Ministry of Education, Nanjing 210009, PR China. dibin@cpu.edu.cn 1620174420@cpu.edu.cn.
Abstract
RATIONALE: Inflammatory bowel diseases (IBDs) are still awaiting innovative treatments that can maximize the efficiency of site-specific drug release in the colon while enhancing intestinal homeostasis. METHODS: Herein, we present multilayer-coated mesoporous silica (MSs) which release payload drugs specifically in the colon tract in the presence of azoreductase produced by the gut microbiota, and simultaneously rejuvenate the tryptophan metabolism of the microbiome to induce activation of the aryl hydrocarbon receptor (AHR) for increased anti-inflammatory effects. The MSs were prepared by using cucurbit[8]uril (CB[8]) as a supramolecular "handcuff" to assemble chitosan/hyaluronic acid multilayers on the periphery of a mesoporous silica core. RESULTS: Strikingly, although MSs remained fairly stable in both acidic and neutral pH, they exhibited excellent responsiveness towards dithionite, an azo-reducing agent employed as a substitute to mimic the specific azoreductase environment in vitro. In comparison with the drug in its free form, hydrocortisone-loaded MSs showed optimized accumulation of therapeutics in the colonic mucosa with minimized premature release in the upper gastrointestinal tract in in vivo imaging and biodistribution studies. The enhanced therapeutic effects of MSs were confirmed in dextran sodium sulfate-induced colitis in mice with promoted colonic epithelial barrier integrity, elevated level of AHR agonists and modulated production of inflammatory cytokines. Furthermore, 16S rRNA analysis showed that the disrupted gut homeostasis of colitic mice was partly corrected by MSs. CONCLUSION: This novel drug delivery system using self-assembly of tryptophan-functionalized chitosan, which was precomplexed with CB[8], and azobenzene-functionalized hyaluronic acid on the surface of mesoporous silica nanoparticles provides a synergistic gut microbiota-targeting approach for IBD therapy.
RATIONALE: Inflammatory bowel diseases (IBDs) are still awaiting innovative treatments that can maximize the efficiency of site-specific drug release in the colon while enhancing intestinal homeostasis. METHODS: Herein, we present multilayer-coated mesoporous silica (MSs) which release payload drugs specifically in the colon tract in the presence of azoreductase produced by the gut microbiota, and simultaneously rejuvenate the tryptophan metabolism of the microbiome to induce activation of the aryl hydrocarbon receptor (AHR) for increased anti-inflammatory effects. The MSs were prepared by using cucurbit[8]uril (CB[8]) as a supramolecular "handcuff" to assemble chitosan/hyaluronic acid multilayers on the periphery of a mesoporous silica core. RESULTS: Strikingly, although MSs remained fairly stable in both acidic and neutral pH, they exhibited excellent responsiveness towards dithionite, an azo-reducing agent employed as a substitute to mimic the specific azoreductase environment in vitro. In comparison with the drug in its free form, hydrocortisone-loaded MSs showed optimized accumulation of therapeutics in the colonic mucosa with minimized premature release in the upper gastrointestinal tract in in vivo imaging and biodistribution studies. The enhanced therapeutic effects of MSs were confirmed in dextran sodium sulfate-induced colitis in mice with promoted colonic epithelial barrier integrity, elevated level of AHR agonists and modulated production of inflammatory cytokines. Furthermore, 16S rRNA analysis showed that the disrupted gut homeostasis of colitic mice was partly corrected by MSs. CONCLUSION: This novel drug delivery system using self-assembly of tryptophan-functionalized chitosan, which was precomplexed with CB[8], and azobenzene-functionalized hyaluronic acid on the surface of mesoporous silica nanoparticles provides a synergistic gut microbiota-targeting approach for IBD therapy.