NANOPARTICLE-ENCAPSULATED BROMODOMAIN-CONTAINING PROTEIN 4 INHIBITORS FOR THERAPEUTICS OF INFLAMMATORY BOWEL DISEASE

Abstract

Abstract Ulcerative Colitis (UC) and Crohn’s disease (CD), the two major types of inflammatory bowel disease (IBD), are chronic diseases with recurrent symptoms and significant morbidity. Long-term persistence of chronic inflammation in IBD is among the major factors contributing to neoplastic transformation and the development of colitis-associated colorectal cancer. There exists a lack of efficient medications for IBD, primarily due to either limited efficacy or side effects. Targeting bromodomain-containing protein 4 (BRD4) represents a novel therapeutic strategy for IBD. Recently, we have successfully identified proprietary, highly potent, and specific BRD4 inhibitors which significantly suppressed the initiation of mucosal inflammation and chronicity in proof-of-concept studies in several animal models of IBD. One of the most pressing challenges in current IBD research is to develop technologies to enable mucosal targeted drug delivery systems that enhance efficacy and decrease side effects. Intriguingly, we found that local delivery of our first-generation BRD4 inhibitors encapsulated in nanoparticles can achieve significantly higher in vivo efficacy at much lower doses than that attained by systemic administration. Local delivery of nanoparticle-encapsulated BRD4 inhibitors by designing nanoparticles that bind to inflamed epithelium would offer superior pharmacotherapy for IBD with higher efficacy, specific delivery, long-lasting release, and a better therapeutic and safety window. We have successfully encapsulated our BRD4 inhibitors in biodegradable nanoparticles with excellent encapsulation efficiency and favorable particle size. Our new generation of BRD4 inhibitors ZL0513, ZL0742, and ZL0591 were encapsulated by a modified solvent displacement method using a polymeric matrix of PEGylated poly (lactic-co-glycolic acid) (PLGA). To evaluate their potential cytotoxic effects, we incubated human colonic epithelial cells (HCECs) and peripheral blood mononuclear cells (PBMCs) with PEGylated-PLGA-ZL0513, ZL0591, and ZL0742 overnight. No apparent increase in cell death was detected in HCECs or PBMCs even at 40 μM. Furthermore, oral administration of our nano-encapsulated BRD4 inhibitors at the dosage of 2 mg/kg effectively block colonic inflammation in both IBD animal models of dextran sulfate sodium (DSS)-induced colitis and oxazolone (OXA)-induced colitis. Collectively, our compelling in vivo efficacy data support that our nano-encapsulated BRD4 inhibitors effectively block colonic inflammation in animal models of IBD. Local delivery of nanoparticle-encapsulated BRD4 inhibitors may offer superior pharmacotherapy for IBD patients. Funding support: Crohn’s & Colitis Foundation Entrepreneurial Investing (EI) Initiative award and Litwin IBD Pioneers Program award from the Crohn’s & Colitis Foundation of America.