title: Colon-targeted cell-permeable NFκB inhibitory peptide is orally active against experimental colitis.
abstract: For the purpose of development of orally active peptide therapeutics targeting NFκB for treatment of inflammatory bowel disease (IBD), two major barriers in oral delivery of therapeutic peptides, metabolic lability and tissue impermeability, were circumvented by introduction of a colon-targeted delivery system and cell permeable peptides (CPP) to NFκB inhibitory peptides (NIP). Suppression of NFκB activation was compared following treatment with various CPP conjugated NIPs (CPP-NIP). The most potent CPP-NIP was loaded in a capsule coated with a colon specific polymer, which was administered orally to colitic rats. The anti-inflammatory activity of the colon-targeted CPP-NIP was evaluated by measuring inflammatory indices in the inflamed colonic tissue. For confirmation of the local action of the CPP-NIP, the same experiment was done after rectal administration. Tissue permeability of the CPP-NIP was examined microscopically and spectrophotometrically using FITC-labeled CPP-NIP (CPP-NIP-FITC). NEMO binding domain peptide (NBD, TALDWSWLQTE) fused with a cell permeable peptide CTP (YGRRARRRARR), CTP-NBD, was most potent in inhibiting NFκB activity in cells. Colon-targeted CTP-NBD, but not colon-targeted NBD and CTP-NBD in an enteric capsule, ameliorated the colonic injury, which was in parallel with decrease in MPO activity and the levels of inflammatory mediators. Intracolonic treatment with CTP-NBD alleviated rat colitis and improved all the inflammatory indicators. CTP-NBD-FITC was detected at much greater level in the inflamed tissue than was NBD-FITC. Taken together, introduction of cell permeability and colon targetability to NIP may be a feasible strategy for an orally active peptide therapy for treatment of IBD.
authors.affiliation: College of Pharmacy, Department of Molecular Biology, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Sungchae
authors.initials: S
authors.lastname: Hong
authors.forename: Soohwan
authors.initials: S
authors.lastname: Yum
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Yoo
authors.forename: Sookjin
authors.initials: S
authors.lastname: Kang
authors.forename: Jeong-Hyun
authors.initials: JH
authors.lastname: Yoon
authors.forename: Dosik
authors.initials: D
authors.lastname: Min
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Kim
authors.forename: Yunjin
authors.initials: Y
authors.lastname: Jung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000627:therapeutic use; D015153:Blotting, Western; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry*; D003106:Colon / Q000187:drug effects / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D043183:Irritable Bowel Syndrome / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use*; D051381:Rats; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity
chemical_list: D000893:Anti-Inflammatory Agents; D057846:Cell-Penetrating Peptides; D016328:NF-kappa B; D010455:Peptides; D014302:Trinitrobenzenesulfonic Acid