Targeted delivery of Nitric Oxide triggered by α-Glucosidase to Ameliorate NSAIDs-induced Enteropathy
Xianglu Wang,
Jiarui Shi,
Zhixin Xu,
Dan Wang,
Yuguang Song,
Guifang Han,
Bangmao Wang,
Hailong Cao,
Yangping Liu,
Jingli Hou
Affiliations
Xianglu Wang
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China; Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China
Jiarui Shi
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
Zhixin Xu
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
Dan Wang
Department of Pathology, General Hospital, Tianjin Medical University, Tianjin, China
Yuguang Song
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
Guifang Han
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China
Bangmao Wang
Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China; Corresponding author.
Hailong Cao
Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China; Corresponding author.
Yangping Liu
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China; Corresponding author.
Jingli Hou
The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Key Laboratory of Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China; Corresponding author.
Nonsteroidal anti-inflammatory drugs (NSAIDs) increase risks of severe small intestinal injuries. Development of effective therapeutic strategies to overcome this issue remains challenging. Nitric oxide (NO) as a gaseous mediator plays a protective role in small intestinal injuries. However, small intestine-specific delivery systems for NO have not been reported yet. In this study, we reported a small intestine-targeted polymeric NO donor (CS–NO) which was synthesized by covalent grafting of α-glucosidase-activated NO donor onto chitosan. In vitro and in vivo experiments demonstrated that CS-NO could be activated by intestinal α-glucosidase to release NO in the small intestine. Pre-treatment of mice with CS-NO significantly alleviated small intestinal damage induced by indomethacin, as demonstrated by down-regulation of the levels of pro-inflammatory cytokines and chemokines CXCL1/KC. Moreover, CS-NO also attenuated indomethacin-induced gut barrier dysfunction as evidenced by up-regulation of the levels of tight junction proteins and restoration of the levels of goblet cells and MUC2 production. Meanwhile, CS-NO effectively restored the defense function of Paneth cells against pathogens in small intestine. Our present study paves the way to develop NO-based therapeutic strategy for NSAIDs-induced small intestinal injuries.
