title: Immunomodulation of cystic fibrosis epithelial cells via NF-κB decoy oligonucleotide-coated polysaccharide nanoparticles.
abstract: Activation of the transcription factor nuclear factor-kappa B (NF-κB) signaling pathway is associated with enhanced secretion of pro-inflammatory mediators and is thought to play a critical role in diseases hallmarked by inflammation, including cystic fibrosis (CF). Small nucleic acids that interfere with gene expression have been proposed as promising therapeutics for a number of diseases. However, applications have been limited by low cellular penetration and a lack of stability. Nano-sized carrier systems have been suggested as a means of improving the effectiveness of nucleic acid-based treatments. In this study, we successfully coated polysialic acid-N-trimethyl chitosan (PSA-TMC) nanoparticles with NF-κΒ decoy oligonucleotides (ODNs). To demonstrate anti-inflammatory activity, the decoy ODN-coated PSA-TMC nanoparticles were administered to an in vitro model of CF generated via interleukin-1β or P. aeruginosa lipopolysaccharides stimulation of IB3-1 bronchial epithelial cells. While free ODN and PSA-TMC nanoparticles coated with scrambled ODNs did not have substantial impacts on the inflammatory response, the decoy ODN-coated PSA-TMC nanoparticles were able to reduce the secretion of interleukin-6 and interleukin-8, pro-inflammatory mediators of CF, by the epithelial cells, particularly at longer time points. In general, the results suggest that NF-κB decoy ODN-coated TMC-PSA nanoparticles may serve as an effective method of altering the pro-inflammatory environment associated with CF.
authors.affiliation: Syracuse Biomaterials Institute, Syracuse University, 318 Bowne Hall, Syracuse, New York, 13244; Department of Biomedical and Chemical Engineering, Syracuse University, 121 Link Hall, Syracuse, New York, 13244.
authors.forename: Patricia R
authors.initials: PR
authors.lastname: Wardwell
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Bader
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002460:Cell Line; D048271:Chitosan / Q000737:chemistry; D020099:Coated Materials, Biocompatible / Q000737:chemistry*; D003550:Cystic Fibrosis / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D017930:Genes, Reporter; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects*; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011134:Polysaccharides / Q000737:chemistry*; D051381:Rats; D012794:Sialic Acids / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D020099:Coated Materials, Biocompatible; D015850:Interleukin-6; D016209:Interleukin-8; C118071:N-trimethyl chitosan chloride; D016328:NF-kappa B; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D011134:Polysaccharides; D012794:Sialic Acids; C021319:polysialic acid; D048271:Chitosan; D008156:Luciferases
keywords: NF-κB; cystic fibrosis; immunomodulation; nanoparticles; oligonucleotides