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In Vivo Efficacy of a Peptide Nanomedicine and In Vitro Testing of a Potential Oral Formulation for the Treatment of Inflammatory Bowel Disease
Author(s) -
Jayawardena Dulari,
Anbazhagan Arivarasu N,
Onyuksel Hayat,
Dudeja Pradeep K
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.764.1
Subject(s) - vasoactive intestinal peptide , inflammatory bowel disease , in vivo , colitis , medicine , nanomedicine , gastroenterology , pharmacology , in vitro , immunology , chemistry , biology , biochemistry , materials science , disease , nanoparticle , nanotechnology , receptor , microbiology and biotechnology , neuropeptide
Inflammatory bowel disease (IBD) is an unmet medical need with increasing incidence worldwide. We have previously demonstrated that the nanomedicine, vasoactive intestinal peptide in sterically stabilized micelles (VIP‐SSM) was superior over the free peptide in alleviating experimental colitis in mice after intra peritoneal injection. In the current studies, we aimed to: i) establish the efficacy of VIP‐SSM when administered locally into the colonic lumen in mice; and ii) conduct in vitro release studies of a potential oral formulation containing the freeze‐dried powder packaged in enteric coated capsules. Methods VIP‐SSM nanomedicine was prepared in saline and was characterized for its size with dynamic light scattering (DLS). Colitis was induced in male C57Bl/6 mice with 3.5%W/V dextran sulfate sodium (DSS) in drinking water for 7 days. Intra rectal treatments of VIP‐SSM, free VIP peptide or vehicle were administered to the colon on day 5 and mice (n=10 per group) were sacrificed on day 10. Alleviation of inflammation was assessed by analyzing colonic tissue histology, colonic goblet cell count, mRNA expression of cytokines and diarrheal phenotype. Based on the effective mouse dose, allometric pharmacokinetic formula was used to calculate human equivalent dose (HED). HED containing nanomedicine was prepared, freeze‐dried and was filled into commercially available enteric coated capsules to perform in vitro release studies at colonic pH. Results Hydrodynamic particle size of VIP‐SSM was approximately 15 nm. The diarrheal phenotype seen with DSS colitis indicated by loose stool in colon as well as the reduced length of colon were alleviated with VIP‐SSM. In parallel, reduced expression of the ion transporter SLC26A3 or down regulated in adenoma (DRA) observed 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 affected distal colonic histology and goblet cell loss observed in DSS colitis mice was also significantly alleviated with VIP‐SSM treatment. VIP‐SSM nanomedicine can be freeze‐dried into a powder which can be reconstituted in water to reform micelles. VIP‐SSM containing capsules at HED, were completely dissolved at pH 6 after 30 minutes giving rise to micelles with active VIP. These capsules with freeze‐dried VIP‐SSM were stable up to 6 weeks when stored in air tight glass containers at 4°C. The capsules dissolved at each time point showed reproducible release profiles with micelles and active VIP. Conclusions Our results demonstrated that local administration of VIP nanomedicine was effective in alleviating colonic inflammation and associated diarrhea in a mouse model of DSS colitis. In vitro results showed promise of a novel oral peptide nanomedicine formulation in enteric coated capsules which can release active VIP into the colonic milieu for potential alleviation of colonic inflammation in humans. Support or Funding Information NIH NIDDK Department of Veterans Affairs This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .