Vasoactive Intestinal Peptide Nanomedicine for the Treatment of Inflammatory Bowel Disease
1:30 pm - 2:30 pm, March 15, 2018
Department of Biopharmaceutical Sciences presents: Dissertation Defense Seminar
"Vasoactive Intestinal Peptide Nanomedicine for the Treatment of Inflammatory Bowel Disease"
Dulari Jayawardena, PhD candidate, BPS Graduate Student
ADVISOR: Prof. Hayat Onyuksel
March 15, 2018 (Thursday)
1:30 PM – 2:30 PM
Room B36 / E221 Rockford
833 S. Wood Street
: Vasoactive intestinal peptide (VIP) is an endogenous neuropeptide with a wide array of immunomodulatory properties. VIP has shown benefit 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).However, clinical use of VIP in IBD would be hindered due to its short biological half-life and potential off target effects (hypotension). To overcome these delivery challenges, previously, our laboratory has developed a biocompatible nano-carrier termed sterically stabilized micelles (SSM), to deliver VIP in the active form to diseased sites. The purpose of this study was to determine the therapeutic benefit of VIP nanomedicine (VIP-SSM) in managing IBD. First, utilizing mouse models of colitis resembling both UC (dextran sulfate sodium/DSS induced colitis) and CD (2,4,6-trinitrobenzene sulfonic acid/TNBS induced colitis) the effects of VIP-SSM via ip route were tested. Since IBD is localized to the intestine, delivering VIP-SSM via enteral route would be preferable over parenteral routes. To this end, we first determined the presence of VIP receptors at the target site (colonic lumen). Next, using mouse models of colitis, we determined the effectiveness of administering VIP-SSM directly to the lumen of the colon via intrarectal instillation. Finally, we tested the prospects of developing the nanomedicine for clinical use via an oral formulation by incorporating the freeze-dried nanomedicine into enteric-coated capsules. Our results demonstrated that ip administered VIP-SSM was 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, goblet cell numbers and ion transporter expression which are dysregulated in the distal colon. These beneficial effects were also apparent when the nanomedicine was administered locally, via intrarectal instillation to the colonic lumen, confirming potential for enteral delivery. Furthermore, in vitro studies showed that capsules containing freeze-dried powder of the nanomedicine, when dissolved in colonic pH, reformed micelles and released active VIP in a reproducible manner. Together, our data demonstrate the effectiveness of VIP-SSM as a therapeutic agent to manage IBD and show feasibility of its potential use as a novel oral product.