Local Colonic Delivery of Vasoactive Intestinal Peptide (VIP) Nanomedicine Alleviates Colitis in Mice

Abstract

Inflammatory Bowel Disease (IBD) is an unmet medical need encompassing two entities; Ulcerative Colitis (UC) and Crohn's Disease (CD). We have previously demonstrated the superior therapeutic effects of systemically administered VIP nanomedicine (VIP in sterically stabilized micelles; VIP‐SSM), in alleviating colitis in mice. In addition, we have also characterized a luminally expressed VPAC1 receptor in human and mouse colonic mucosa. Thus, the current studies were undertaken to determine if delivering the nanomedicine directly to the colonic lumen could have similar therapeutic benefits.MethodsVIP‐SSM was prepared by mixing aqueous solutions of lipid and peptide in a predetermined molar ratio and was characterized for its size by dynamic light scattering. Colitis was induced in C57Bl/6 mice with 3.5% w/v dextran sulfate sodium (DSS) in drinking water for 7 days. Animals were randomly divided into 5 groups; (Control, DSS, VIP‐SSM, DSS+VIP‐SSM and DSS+ VIP). On the 5th day mice were anesthetized with ketamine/xylazine and catheterized to intra rectally instill 100 μls of, VIP‐SSM (0.25 nmol), free VIP (0.25 nmol) or SSM (100 nmol). At day 7, mice were switched to tap water and sacrificed at day 10. Body weights of mice were recorded daily. Colon appearance was observed for diarrheal phenotype, distal colonic mucosa was used for RNA and protein isolation for qPCR and western blot analysis, respectively. Frozen sections of colon were used for H & E and immunostaining.ResultsThe prepared nanoparticle hydrodynamic particle sizes were approximately 15 nm. At day 10, VIP‐SSM treated mice showed significant improvement in body weight compared to DSS and free VIP treated DSS mice. The diarrheal phenotype seen with DSS indicated by loose stool in colon and reduced length was alleviated with VIP‐SSM (showing presence of solid fecal pellets) and improved colon length. In parallel, reduced expression of ion transporters such as SLC26a3 or down regulated in adenoma (DRA) seen in colitis was abrogated with VIP‐SSM intra rectal treatment but not with the free VIP peptide. Furthermore, increased pro‐inflammatory cytokine mRNA expression and damaged distal colonic histology and goblet cell loss seen in DSS was also significantly alleviated with VIP‐SSM treatment. The VPAC1 receptor expression was similar across all groups.ConclusionsThese results demonstrate that local administration of VIP nanomedicine is effective in alleviating severe inflammation and associated diarrhea in colitis. Thus, delivering VIP‐SSM nanoparticle orally with site‐specific release to the colon could be a potential option in managing UC in future.Support or Funding InformationNIH/NIDDK, Department of Veteran AffairsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.