Biomaterials approach for targeted therapeutics delivery in inflammatory bowel disease

Pathogenesis of inflammatory bowel diseases (IBD) is associated with continuous episodes of diffusive gut epithelial inflammation and dysregulated mucosal immune response. IBD (with major forms Crohn’s and ulcerative colitis) is the second most common inflammatory condition, affecting 6.8 million people around the globe. Current conventional oral and injectable delivery strategies are well established in the management and therapy of colonic diseases including IBD. However, disadvantages in terms of the inability to target the drugs directly at the diseased tissue, with limited therapeutic efficacy and a high risk of off-targeted drug associated side-effects make replacement of the conventional strategies desirable. Therefore, advanced drug delivery strategies with site-specificity and local delivery to the inflamed colon are essential for effective treatment of intestinal inflammation locally. Site-specific delivery of the drugs to inflamed colon regions can prevent the associated drug systemic toxicities while maintaining therapeutic efficacy. Targeting inflammation regions can ideally be accomplished by developing an ideal drug delivery system that targets unique characters of the colitis tissue. In colitis, intestinal epithelium has the dysregulated mucous layer and a high degree of cationic proteins accumulation, which results cationic charge building up at the colitis surface, providing drug carriers with an anionic surface charge as targeting vehicles. A delivery carrier system with an anionic surface charge with mucoadhesive properties could favourably adhere to the cationic charge of the inflamed surfaces and release the payload locally. An inflammation targeted nanocarrier system (IT/NCs) was fabricated via oral delivery for colitis therapy using cyclosporine A (CsA) immunosuppressant drug. Interestingly, the in vitro (charge- modified surfaces), ex vivo (on human healthy vs colitis biopsies) findings confirmed the preferential adhesion on positive (inflamed) surfaces. Further in vivo (DSS and TNBS colitis mice models) therapeutic efficacy study data have shown that the CsA/IT- NCs system is an encouraging therapeutic approach in the management of colitis. Restoration of barrier functionality by mucosal healing strategies has the potential to be a considered approach in colitis therapy. Nevertheless, although attempts have been made to develop anti-inflammatory, immunomodulatory therapies for patients with IBD have been widespread, treatments for the mucosal repair and tissue homeostasis in IBD are still under investigation, and there are a few commercial products available. Mucosal healing, epithelial restitution and symptom management have become vital goals to maintain the remission levels and eventually to stop the IBD progression as well as extra-intestinal manifestations. By identifying the importance of Hyaluronan (HA) in the mucosal, epithelial matrix component of the intestinal wall, the project also investigated the role of HA-Enema as a non-drug-based device in enhancing the barrier functionalities in colitis. In vitro studies showed that HA-Enema system has shown to decrease inflammation and permeability. Further in vivo DSS colitis mice study revealed that the rectal HA-Enema instillation, which applied as a cementing barrier modulated the intestinal barrier by providing potent anti-inflammatory, permeability reduction response to colitis. The research adds to the current knowledge in inflammation-specific colon-targeted drug delivery strategies, which can also be applied with different small/large molecules delivery in colon-associated disease therapies. In addition, biophysical dysregulated colon wall protecting barrier strategy developed in this project could benefit several patients suffering from colitis.

Funder

Science Foundation Ireland
Horizon 2020

Publisher

NUI Galway

Rights

Attribution-NonCommercial-NoDerivs 3.0 Ireland

cbn

Collections

University of Galway Theses (PhD Theses)