Journal
BIOMACROMOLECULES
Volume 17, Issue 3, Pages 788-797Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biomac.5b01518
Keywords
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Funding
- National Science Foundation [CBET-1033746]
- Fletcher Stuckey Pratt Chair in Engineering
- National Science Foundation Graduate Research Fellowship Program [DGE-1110007]
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Inflammatory bowel diseases (IBD) manifest from excessive intestinal inflammation. Local delivery of siRNA that targets these inflammatory cytokines would provide a novel treatment approach. Micro encapsulated nanogels are designed and validated as platforms for oral delivery of siRNA targeting TNF-alpha, a common clinical target of IBD treatments. The preferred platform was designed to (i) protect siRNA-loaded nanogels from the harsh acidic environment of the upper GI tract and (ii) enzymatically degrade and release the nanogels once the carrier has reached the intestinal region. This platform consists of microgels composed of poly(methacrylic acid-co-N-vinyl-2-pyrrolidone) (P[MAA-co-NVP]) cross-linked with a trypsin-degradable peptide linker. The P(MAA-co-NVP) backbone is designed to collapse around and protect encapsulated nanogel from degradation at the low pH levels seen in the stomach (pH 2-4). At pH levels of 6-7.5, as typically observed in the intestine, the P(MAA-co-NVP) matrix swells, potentially facilitating diffusion of intestinal fluid and degradation of the matrix by intestinal enzymes such as trypsin, thus freeing the therapeutic nanogels for delivery and cellular uptake within the intestine. TNF-alpha siRNA-loaded nanogels released from this platform were capable of inducing potent knockdown of secreted TNF-alpha levels in murine macrophages, further validating the potential for this approach to be used for the treatment of IBD.
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