Vasoactive Intestinal Peptide Nanomedicine for the Treatment of Inflammatory Bowel Disease
thesisposted on 27.07.2018, 00:00 authored by Dulari Jayawardena
Vasoactive intestinal peptide (VIP) is an endogenous neuropeptide with a wide array of immunomodulatory properties. VIP has shown beneficial effects in managing multiple inflammatory disorders, including inflammatory bowel disease (IBD). IBD includes chronic disorders of the gastro intestinal tract, namely Crohn’s disease (CD) and ulcerative colitis (UC). The usage of VIP is hindered by its short biological half-life and off target effects (hypotension). To overcome these delivery challenges, we have developed a biocompatible nano-carrier (SSM), which can successfully deliver active VIP to the target tissue to treat IBD. The studies herein were designed to determine the therapeutic benefit of intra peritoneally (ip) administered VIP nanomedicine, VIP-SSM in managing IBD, utilizing mouse models of colitis resembling both CD (2,4,6-trinitrobenzene sulfonic acid/TNBS induced colitis) and UC (dextran sulfate sodium/DSS induced colitis). Since IBD is an intestinal disease, delivering VIP-SSM via oral route would be more beneficial. To this end, we have tested the effectiveness of administering the nanomedicine intra luminally to the colon. Finally, we tested the prospects of scaling up the nanomedicine for clinical use via oral formulation by incorporating the nanomedicine into enteric-coated capsules. Our results demonstrate that ip administered VIP-SSM is effective in alleviating inflammation associated with both DSS and TNBS colitis. VIP-SSM significantly reduced the inflammation and associated diarrhea in colitis by affecting pro-inflammatory cytokine mRNA expression, histology, tight junction proteins, secreted mucus and ion transporter expression in the distal colon. These beneficial effects were also apparent when the nanomedicine was administered intra rectally to the colonic lumen, showing potential for oral delivery. Furthermore, in vitro studies show that freeze-dried powder of the nanomedicine gives rise to micelles with active VIP, released from capsules in solution. Together, our data indicate the effectiveness of VIP-SSM as a therapeutic agent in managing IBD, and shows proof of concept of its use as a novel oral product.