Design And Activity Evaluation Of Single-drug Or Multidrug Delivery Guanosine Borate Anti-inflammatory Hydrogels

The unique G-quadruplex structure and dynamic borate ester bonding of guanosine borate ester hydrogels have made these gels excellent biocompatible,biodegradable,self-healing,injectable,and controllable responsive to multiple stimuli,and have become attractive biomaterials for topical drug delivery.Inflammatory bowel disease(IBD)is a chronic inflammatory disease with symptoms limited to the distal colon and rectum in most patients,making local rectal drug delivery for IBD a unique advantage.Among them,the clinical effect of Chinese medicine enema for the treatment of IBD is remarkable,but the retention time of traditional Chinese medicine enema preparation is short,the content of active ingredients is low,and patient compliance is poor.The unique properties of guanosine borate hydrogels inspired us to use them as a rectal delivery system loaded with active ingredients of Chinese medicine for the treatment of IBD,which can prolong the drug residence time,protect the intestinal ulcerated tissues,reduce the dosing frequency and enhance the patient’s medication compliance by virtue of the rheological properties of hydrogel.In this work,guanosine and benzene-1,4-diboronic acid were used to construct guanosine borate ester hydrogel as a topical drug delivery system,which was loaded with active ingredients of traditional Chinese medicine in the form of encapsulation or borate ester covalently linked to achieve precise delivery in the form of in situ drug delivery for the treatment of IBD.Firstly,a single drug delivery hydrogel system(GBR)was constructed using the antiinflammatory drug rutin,and then,in order to achieve better therapeutic effects,a multidrug co-delivery hydrogel system(GBD)was constructed using a variety of herbal active ingredients with different IBD therapeutic effects,quercetin,desmethyleneberberine,and dencichine.In the construction of hydrogels,the optimal gel formation conditions were first determined by vial inversion experiments,and then the existence of borate ester bonds and selfassembly mechanism in the gel system were confirmed by NMR,UV-Vis,CD and XRD,and the cross-linked mesh structure of the gel system was confirmed by TEM and AFM.Rheological testing confirmed the good injectability and self-healing properties of the gel system,which can be used as a rectal drug delivery material.The in vitro release and degradation behavior of the gel system in different buffered media indicated that the gel system has dual p H/ROS stimulus responsiveness and is capable of accelerating the drug release in simulated inflammatory environments and increasing the drug concentration in inflammatory regions.In vivo degradation and cytotoxicity experiments demonstrated the good biocompatibility and safety of the gel system.In the mouse model of DSS-induced colitis,the GBR hydrogel showed good therapeutic effects.This study provides a new idea for the treatment of inflammatory bowel disease by enema,and also provides a new local delivery strategy for the active ingredients of the insoluble Chinese medicine.