Colon-Adhering Delivery System with Inflammation Responsiveness for Localized Therapy of Experimental Colitis

• Published in: ACS biomaterials science & engineering 2023-08, Vol.9 (8), p.4781-4793
• Main Authors: Kumar, Ajay, Kanika, Kumar, Vibhu, Ahmad, Anas, Mishra, Rakesh Kumar, Nadeem, Ahmed, Siddiqui, Nahid, Ansari, Md Meraj, Raza, Syed Shadab, Kondepudi, Kanthi Kiran, Khan, Rehan
• Format: Article
• Language: English
• Subjects: Animals; Colitis - chemically induced; Colitis - drug therapy; Colitis, Ulcerative - drug therapy; Controlled Release and Delivery Systems; Hydrogels - therapeutic use; Inflammation - drug therapy; Mice
• ISSN: 2373-9878; 2373-9878
• DOI: 10.1021/acsbiomaterials.3c00480

Ulcerative colitis (UC) is a chronic inflammation-related disease that severely affects the colon and rectum regions. A variety of therapy regimens are used for the treatment of UC. Clinically, therapeutic enema is the choice of therapy for UC patients. Irrespective of on-site administration, the major limitation of therapeutic enemas is the dispossession of the medicine followed by low drug availability for the therapeutic action. In our present work, we have developed an enzyme-responsive injectable hydrogel (ER-hydrogel) to overcome the limitations of therapeutic enema. The hydrogels possess two major advantages, which are being exploited for therapeutic drug delivery in UC: prolonged retention and enzyme responsiveness. The former is one of the prominent advantages of hydrogel compared to free drug enema and the latter controls the release of the drug or provides drug release on-demand. The ER-hydrogel was formulated by the heat-cool method and for therapeutic purposes, a corticosteroid drug, budesonide (Bud), was encapsulated into the ER-hydrogel and evaluated for its various physicochemical and therapeutic potentials in dextran sodium sulfate (DSS)-induced UC. In vitro and ex vivo adhesion studies confirm the retention or mucoadhesive nature of the ER-hydrogel, and the upsurge in Bud release from the Bud-loaded ER-hydrogel upon the addition of esterase enzyme confirms the enzyme-mediated drug release from the ER-hydrogel. Moreover, Bud-loaded ER-hydrogel exhibited promising results in alleviating the disease activity index of UC, and restored the length of the colon, which is the main hallmark of UC. In terms of the health of the colon tissue, the Bud-loaded ER-hydrogel restored the colonic tissue damage, as seen in the H&E-stained, AB-NR-stained, and HID-AB-stained colon sections. Finally, the Bud-loaded ER-hydrogel also markedly subsided the IL-1β, TNF-α, MPO, and nitrite levels in serum and colon tissues. Thus, the fabricated Bud-loaded ER-hydrogel possesses appreciable translational potential due to its ability to significantly ameliorate inflammatory changes compared to naive or water-based therapeutic enema in acute experimental colitis in mice.