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.

Oral Delivery of Biologics for Precision Medicine

“…Knipe and co-workers [122] prepared 2-(diethylamino)ethyl methacrylate (DEAEMA) ( Figure 11B) based nanogels that swell at early endosomal pH (≈5.5), to facilitate the endosomal escape and deliver TNF-α siRNA to the cytosol of macrophages in the inflamed intestinal region. These nanogels were entrapped into microgels made of poly(methacrylic acid-co-N-vinyl-2-pyrrolidone (PMAA-co-NVP) ( Figure 11B) crosslinked by a trypsin-degradable peptide for gastric protection and intestinal release.…”

Tunable poly(methacrylic acid‐co‐acrylamide) nanoparticles through inverse emulsion polymerization

“…Polyionic nanogels are particularly interesting, as these nanoparticles with non‐neutral surface charge are generally stable in aqueous solutions and exhibit predictable responses around their pKa. Our group and others have extensively studied the use of polyanionic and polycationic nanogels for the pH‐responsive drug delivery of small molecules and macromolecular therapeutics in the treatment of cancer, ulcerative colitis, and numerous other diseases . Each of these systems functions by entrapping the payload in a buffer condition where therapeutic‐nanomaterial interactions are favorable, followed by a predictable shift toward unfavorable interaction in the destination's physiological environment.…”

Polymer nanocarriers for MicroRNA delivery

“…With respect to size, nanoscale materials are ideally suited for RNA delivery because they can protect RNA from degradation, extend circulation half‐life, facilitate cellular entry, and increase therapeutic index . Indeed, various nanoparticle (NP) delivery systems have shown considerable promise for the delivery of plasmid DNAs, antisense oligonucleotides, small interfering RNAs (siRNAs), and miRNAs to diseased cells in vitro and in vivo . When considering size as a design parameter for miRNA mimic delivery vehicles, it is important to note that NPs with diameters less than ∼5 nm rapidly undergo renal clearance upon intravenous administration and those with diameters greater than ~200 nm exhibit splenic filtration due to the 200–500 nm size range of interendothelial cell slits .…”

“…Polymer materials have been widely explored as tools to carry therapeutic cargo (e.g., small molecules, peptides, proteins, DNAs, siRNAs, and miRNAs) to specific tissues/cells to intervene in disease . The types of polymers that have been incorporated into delivery vehicles include poly(lactic‐ co ‐glycolic acid) (PLGA), PEG, poly‐ L ‐lysine (PLL), poly‐ L ‐arginine (PLA), PEI, and more.…”