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Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models

INTRODUCTION: The transcription factor nuclear factor-kappa B (NF-κB) is highly involved in regulation of a number of cellular processes, including production of inflammatory mediators. Thus, this transcription factor plays a role in pathology of many diseases, including rheumatoid arthritis, an aut...

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Autores principales: Wardwell, Patricia R., Forstner, Martin B., Bader, Rebecca A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632484/
https://www.ncbi.nlm.nih.gov/pubmed/26531309
http://dx.doi.org/10.1186/s13075-015-0824-x
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author Wardwell, Patricia R.
Forstner, Martin B.
Bader, Rebecca A.
author_facet Wardwell, Patricia R.
Forstner, Martin B.
Bader, Rebecca A.
author_sort Wardwell, Patricia R.
collection PubMed
description INTRODUCTION: The transcription factor nuclear factor-kappa B (NF-κB) is highly involved in regulation of a number of cellular processes, including production of inflammatory mediators. Thus, this transcription factor plays a role in pathology of many diseases, including rheumatoid arthritis, an autoimmune disease hallmarked by an imbalance of pro and anti-inflammatory cytokines. Small nucleic acids with sequences that mimic the native binding site of NF-κB have been proposed as treatment options for RA; however due to low cellular penetration and a high degree of instability, clinical applications of these therapeutics have been limited. METHODS: Here, we describe the use of N-trimethyl chitosan-polysialic acid (PSA-TMC) nanoparticles coated with decoy oligodeoxynucleotides (ODNs) specific to transcription factor NF-κB (PSA-TMC-ODN) as a method to enhance the stability of the nucleic acids and facilitate increased cellular penetration. In addition to decoy ODN, PSA-TMC nanoparticles were loaded with RA therapeutic methotrexate (MTX), to assess the anti-inflammatory efficacy of a combination therapy approach. Two different in vitro models, a cell line based model as well as a primary RA cell model were used to investigate anti-inflammatory activity. One way ANOVA followed by Holm-Sidak stepdown comparisons was used to determine statistical significance. RESULTS: In general, free ODN did not significantly affect secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8, (IL-8) while free MTX had variable efficacy. However, PSA-TMC-ODN and PSA-TMC-ODN-MTX resulted in significant decreases in the inflammatory mediators IL-6 and IL-8 in both cell models. In addition, PSA-TMC exhibited sufficient cellular uptake, as observed through fluorescence microscopy. CONCLUSIONS: These results support our previous findings that PSA-TMC nanoparticles are an effective delivery vehicle for small nucleic acids, and effectively alter the pro-inflammatory state characteristic of RA.
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spelling pubmed-46324842015-11-05 Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models Wardwell, Patricia R. Forstner, Martin B. Bader, Rebecca A. Arthritis Res Ther Research Article INTRODUCTION: The transcription factor nuclear factor-kappa B (NF-κB) is highly involved in regulation of a number of cellular processes, including production of inflammatory mediators. Thus, this transcription factor plays a role in pathology of many diseases, including rheumatoid arthritis, an autoimmune disease hallmarked by an imbalance of pro and anti-inflammatory cytokines. Small nucleic acids with sequences that mimic the native binding site of NF-κB have been proposed as treatment options for RA; however due to low cellular penetration and a high degree of instability, clinical applications of these therapeutics have been limited. METHODS: Here, we describe the use of N-trimethyl chitosan-polysialic acid (PSA-TMC) nanoparticles coated with decoy oligodeoxynucleotides (ODNs) specific to transcription factor NF-κB (PSA-TMC-ODN) as a method to enhance the stability of the nucleic acids and facilitate increased cellular penetration. In addition to decoy ODN, PSA-TMC nanoparticles were loaded with RA therapeutic methotrexate (MTX), to assess the anti-inflammatory efficacy of a combination therapy approach. Two different in vitro models, a cell line based model as well as a primary RA cell model were used to investigate anti-inflammatory activity. One way ANOVA followed by Holm-Sidak stepdown comparisons was used to determine statistical significance. RESULTS: In general, free ODN did not significantly affect secretion of pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-8, (IL-8) while free MTX had variable efficacy. However, PSA-TMC-ODN and PSA-TMC-ODN-MTX resulted in significant decreases in the inflammatory mediators IL-6 and IL-8 in both cell models. In addition, PSA-TMC exhibited sufficient cellular uptake, as observed through fluorescence microscopy. CONCLUSIONS: These results support our previous findings that PSA-TMC nanoparticles are an effective delivery vehicle for small nucleic acids, and effectively alter the pro-inflammatory state characteristic of RA. BioMed Central 2015-11-04 2015 /pmc/articles/PMC4632484/ /pubmed/26531309 http://dx.doi.org/10.1186/s13075-015-0824-x Text en © Wardwell et al. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Wardwell, Patricia R.
Forstner, Martin B.
Bader, Rebecca A.
Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
title Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
title_full Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
title_fullStr Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
title_full_unstemmed Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
title_short Investigation of the cytokine response to NF-κB decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
title_sort investigation of the cytokine response to nf-κb decoy oligonucleotide coated polysaccharide based nanoparticles in rheumatoid arthritis in vitro models
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4632484/
https://www.ncbi.nlm.nih.gov/pubmed/26531309
http://dx.doi.org/10.1186/s13075-015-0824-x
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