DEVELOPMENT OF NANOPARTICLE-ENCAPSULATED BRD4 INHIBITORS FOR NOVEL EPIGENETIC THERAPEUTICS OF IBD

Abstract

Abstract BACKGROUND Inflammatory bowel diseases (IBD) are chronic intestinal disorders that are typically categorized as one of two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). We have found that epigenetic regulator bromodomain-containing protein 4 (BRD4) is critical in controlling expression of IBD-associated inflammatory cytokine networks. Targeting BRD4 represents a novel therapeutic strategy by modulating IBD-associated inflammatory networks for effective treatment of IBD. Previously, we have successfully identified highly potent and specific BRD4 inhibitors which significantly suppressed colonic mucosal inflammation and chronicity 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. At current study, we further examined the in vivo efficacy of our nano-encapsulated BRD4 inhibitors on animal models of IBD as well as their in vivo and in vitro safety evaluation. METHODS BRD4 inhibitors were encapsulated into biodegradable nanoparticles by a modified solvent displacement method using a polymeric matrix of PEGylated poly (lactic-co-glycolic acid) (PLGA). Drug metabolism/pharmacokinetic (DMPK) profiling of these Nano-BRD4 inhibitors were examined for their in vivo drug release test and in vitro safety evaluation. In vivo efficacy of Nano-BRD4 inhibitors were evaluated in IBD animal models of both dextran sulfate sodium (DSS)-induced acute or chronic colitis, oxazolone (OXA)-induced colitis and Cbir1 T Cell Transfer-induced colitis. RESULTS Drug release test in vivo and in vitro safety evaluation of Nano-BRD4 inhibitors indicate their good DMPK potential and low toxicity. Oral administration of Nano-BRD4 inhibitors at the dosage of 1 mg/kg effectively block colonic inflammation in both DSS-induced acute or chronic colitis, OXA-induced colitis and Cbir1 T Cell Transfer-induced colitis of mice. Nano-BRD4 inhibitors significantly reduced mucosal inflammation and restores tissue architecture in colon of IBD animal models. Furthermore, Nano-BRD4 inhibitors blocked DSS-, OXA-, and Cbir1 T Cell Transfer-induced induced expression of inflammatory cytokine. CONCLUSION Our nano-encapsulated BRD4 inhibitors effectively block colonic inflammation in our established multiple animal models of IBD. Drug release test in vivo and in vitro safety evaluation of Nano-BRD4 inhibitors indicate their good DMPK potential and low toxicity. Local delivery of nanoparticle-encapsulated BRD4 inhibitors would offer superior epigenetic pharmacotherapy for IBD with higher efficacy, specific delivery, long-lasting release, and a better therapeutic and safety window. FUNDING SUPPORT Litwin IBD Pioneers Program and Entrepreneurial Investing (EI) Initiative award from the Crohn’s & Colitis Foundation of America.