Acid-tolerant and hypoxia-responsive drug delivery system based on sulphobetaine-modified azocalix[4]arene for treating ulcerative colitis

Abstract

Oral administration has been considered a conventional therapeutic strategy for ulcerative colitis (UC) due to better safety profiles, convenience of administration and high patient compliance. However, the application faces challenges of premature drug release and degradation in the harsh gastrointestinal environment, resulting in a diminished therapeutic efficacy. Herein, we customized an acid-stable and hypoxia-responsive macrocyclic carrier, zwitterionic sulphobetaine modified azocalix[4]arene (SBAC4A). SBAC4A possesses the hypoxia-responsiveness ability due to the azo groups, the acid resistance ability in the acidic environment because of the zwitterionic parts and phenolic-OH groups, and the capacity for effective internalization by colon epithelial cells on account of its zwitterionic nature. By loading sulfasalazine (SF), the resultant supramolecular nanoformulation SF@SBAC4A demonstrates enhanced anti-inflammatory efficacy. When applied in UC in vivo, the therapeutic effect of SF@SBAC4A was significantly enhanced compared to free SF, as it effectively alleviated colon inflammation and promoted mucosal repairment. Importantly, this design principle provides a supramolecular strategy for developing oral delivery systems for anti-inflammatory drugs.