Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Abstract

has been regarded as an alternative strategy to treat IBD by downregulating TNF-α levels produced by the activated macrophages. [17][18][19][20] However, the success of RNAi has to mainly rely on the gene carriers to protect the target genes. Many researchers have been working on the discovery of drug and gene carriers with high efficiency and biocompatibility. [21][22][23][24][25] Electrostatic condensation of macromolecular genes into nanoparticles by cationic carriers has been acknowledged to be a common strategy for the nonviral delivery. [26][27][28] As reported, polycations acting as gene carriers possess such limitation as lack of superior biocompatibility, insufficient release of delivered genes, easy absorption, and quick elimination in the bloodstream. [29][30][31][32] Therefore, developing new delivery strategies is necessitated to substantially overcome these shortcomings for promoting application of RNAi technology.Polysaccharides such as schizophyllan, curdlan, yeast glucan, lentinan, and auricularian have been introduced as soft matrices to accommodate inorganic nanoparticles, fluorescent dyes, drugs, and oligonucleotides for versatile therapeutic functions due to their unique structural characteristics. [33] Of these, lentinan (LNT for short) has been demonstrated to exist as a triple helix (denoted t-LNT) in water and as a single flexible chain (denoted s-LNT) under such conditions as in dimethyl sulfoxide (DMSO), [34,35] in aqueous sodium hydroxide (NaOH) solution with the NaOH concentration higher than 0.08 m, [36] and in water at the temperature of higher than 135 °C. [37] When the DMSO content decreases gradually through adding water or dialysis against water, the s-LNT chains reassemble into the triple helix (denoted r-LNT) owing to the hydrophobic and hydrogen bonding interactions. [38] Moreover, when single polydeoxyadenylic acid (poly(dA)) chains are added during the reassembling process of s-LNT, two s-LNT chains are able to selectively combine a poly(dA) chain via hydrogen bonding to form a novel triple helical hybrid (denoted s-LNT/ poly(dA)) with high thermal stability under the physiological condition, [39] effectively protecting poly(dA) from degradation. Based on these findings, we have established a promising gene delivering vehicle based on the s-LNT/poly(dA) nanocomposite, in which an immune gene of CpG DNA was linked with a poly(dA) tail through a disulfide bond to stimulate IL-12p40 Tumor necrosis factor alpha (TNF-α) 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-α (PS-ATNF-α), targeting the intestinal inflammation based on the interaction of the single chain of triple helical β-glucan (s-LNT) with polydeoxyadenylic acid [poly(dA)], and the colon-specific degradation of chitosanalginate (CA) hydrogel, is reported. The target gene of PS-ATNF-α, with a poly(dA) tail through a disulfide bond (-SS-), interacts with s-LNT to form a r...

Review: Local Tumor Necrosis Factor-α Inhibition in Inflammatory Bowel Disease

“…CAL-ASO is also a formulation using ISIS 25302, which is complexed with lentinan and encapsulated in a chitosan–alginate hydrogel [ 116 ]. The complexion with lentinan protects the ASO from degradation while the chitosan–alginate hydrogel yields an oral colon-targeted formulation.…”

Oral Delivery of Biologics in Inflammatory Bowel Disease Treatment

“…Blocking CD154/CD40 interactions (Gao et al, 2005) Intracolonic TNF-α (Duan et al, 2019) Oral an N-terminal deletion mutant of monocyte chemoattractant protein-1 for oral delivery. This approach alleviated colitis in DSS-induced mice models (Palffy et al, 2011).…”

“…In this study, AON against TNF-α was delivered via polysaccharide-based NPs. The oral-delivered NPs reduce TNF-α production by 36.4% in DSS-induced mice model ( Duan et al, 2019 ).…”

Drug Targeting of Inflammatory Bowel Diseases by Biomolecules

“…The co-delivery of pro-resolving factors could become a promising strategy for oral therapy of inflamed colon. Recently, phosphorothiolated antisense oligodeoxyribonucleotides of TNF-α were embedded in the same chitosan–alginate hydrogel, aiming for intestinal inflammation control [ 152 ]. The nanocarrier containing about 83.5% of the oligonucleotide was administered orally in a DSS-induced inflammation mice model.…”