Journal
ADVANCED HEALTHCARE MATERIALS
Volume 8, Issue 5, Pages -Publisher
WILEY
DOI: 10.1002/adhm.201801389
Keywords
antisense oligonucleotides; intestinal inflammation; oral administration; polysaccharides; TNF-alpha
Funding
- National Natural Science Foundation of China [21574102, 21274114]
- National Key Research and Development Plan [2016YFD0400202]
- Major Program of National Natural Science Foundation of China [21334005]
- New Century Excellent Talents Program of Education Ministry [NCET-13-0442]
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Tumor necrosis factor alpha (TNF-alpha) is usually regarded as a potential target for inflammatory bowel disease therapy. Herein, a promising strategy for effective delivery of phosphorothioated antisense oligodeoxyribonucleotide of TNF-alpha (PS-ATNF-alpha), targeting the intestinal inflammation based on the interaction of the single chain of triple helical beta-glucan (s-LNT) with polydeoxyadenylic acid [poly(dA)], and the colon-specific degradation of chitosan-alginate (CA) hydrogel, is reported. The target gene of PS-ATNF-alpha, with a poly(dA) tail through a disulfide bond (-SS-), interacts with s-LNT to form a rod-like nanocomposite of s-LNT/poly(dA)-SS-PS-ATNF-alpha, which significantly inhibits lipopolysaccharide (LPS)-induced TNF-alpha at the protein level by 38.2% and mRNA level by 48.9% in RAW264.7 macrophages. The nanocomposites carried by the CA hydrogel with the loading amount of 83.5% are then orally administered and specifically released to the inflamed intestine, followed by internalization into intestinal cells such as macrophages, to reduce TNF-alpha production by 36.4% and dextran sulfate sodium-induced inflammation by decreasing myeloperoxidase and malondialdehyde. This study defines a new strategy for the oral delivery of antisense oligonucleotides to attenuate inflammatory response, demonstrating a notable potential for clinical applications in intestine-inflammation-targeted therapy.
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