title: Enzyme- and pH-Responsive Microencapsulated Nanogels for Oral Delivery of siRNA to Induce TNF-α Knockdown in the Intestine.
abstract: Inflammatory bowel diseases (IBD) manifest from excessive intestinal inflammation. Local delivery of siRNA that targets these inflammatory cytokines would provide a novel treatment approach. Microencapsulated nanogels are designed and validated as platforms for oral delivery of siRNA targeting TNF-α, 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-α siRNA-loaded nanogels released from this platform were capable of inducing potent knockdown of secreted TNF-α levels in murine macrophages, further validating the potential for this approach to be used for the treatment of IBD.
authors.affiliation: Department of Chemical Engineering, C0400, The University of Texas at Austin , Austin, Texas 78712, United States.|Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Knipe
authors.affiliation: Department of Biomedical Engineering, C0800, The University of Texas at Austin , Austin, Texas 78712, United States.|Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Strong
authors.affiliation: Department of Chemical Engineering, C0400, The University of Texas at Austin , Austin, Texas 78712, United States.|Department of Biomedical Engineering, C0800, The University of Texas at Austin , Austin, Texas 78712, United States.|Department of Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin , Austin, Texas 78712, United States.|College of Pharmacy, A1900, The University of Texas at Austin , Austin, Texas 78712, United States.|Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, The University of Texas at Austin , Austin, Texas 78712, United States.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Peppas
mesh_terms: D000818:Animals; D002214:Capsules / Q000737:chemistry*; D002460:Cell Line; D020100:Hydrogels / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D049329:Nanostructures / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D011109:Polymethacrylic Acids / Q000737:chemistry; D011760:Pyrrolidinones / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D014357:Trypsin / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D002214:Capsules; D020100:Hydrogels; D009842:Oligopeptides; D011109:Polymethacrylic Acids; D011760:Pyrrolidinones; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C042670:N-vinyl-2-pyrrolidinone; D014357:Trypsin