Intra-articular Retention and Anti-arthritic Effects in Collagen-Induced Arthritis Model Mice by Injectable Small Interfering RNA Containing Hydrogel

Abstract

Small interfering RNAs (siRNAs) are expected to offer a means of treating rheumatoid arthritis (RA) because they allow the specific silencing of genes related to RA pathogenesis. In our previous study, we reported that the siRNA targeted against RelA (anti-RelA siRNA), an important nuclear factor-kappaB (NF-κB) subdomain, was an effective therapeutic in atopic dermatitis and RA model animals. In this study, to develop an intra-articular injectable gel formulation against RA, we prepared a hydrogel that contains anti-RelA siRNA, and determined the in vitro release profile (%) and in vivo intra-articular retention of fluorescence-labeled model siRNA, and the anti-arthritic effects of the anti-RelA siRelA containing hydrogel in RA model mice. We selected the silk protein, sericin (SC), as an aqueous gel base, as it is a biocompatible and useful for forming hydrogels without a cross-linker. We showed that fluorescence-labeled model siRNA was continuously released from SC hydrogel in vitro, and retained in the knee joint of rats after injection of siRNA hydrogel. In addition, the knee joint thickness, clinical severity and incidence (%) in collagen-induced arthritis (CIA) mice as RA model treated with anti-RelA siRNA containing hydrogel were more improved than untreated, anti-RelA siRNA solution and negative control siRNA containing hydrogel group. Therefore, the intra-articular injectable sericin hydrogel formulation containing of anti-RelA siRNA could be a great potential therapeutic in rheumatoid arthritis.

Anti-RelA siRNA-Encapsulated Flexible Liposome with Tight Junction-Opening Peptide as a Non-invasive Topical Therapeutic for Atopic Dermatitis

“…The siRelA suppresses RelA, which is closely associated with allergy induction. 32) We also confirmed the therapeutic efficacy of siRelA in model mice with immuno-disorders using rheumatoid arthritis and AD models. 9,10,12,28,33,34) In this study, we developed an siRNA-encapsulated DOPE/ CHEMS flexible liposome with AT1002 as an effective dermally applied siRNA delivery and RNAi therapeutic system, and determined the intracellular siRNA uptake ability and cytotoxicity in macrophages of siRNA-encapsulated flexible liposomes.…”

“…NF-κB is overproduced in immunocompetent dendritic cells and macrophages, and regulates the expression of various inflammation-related molecules, including the inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α. [29][30][31] RelA (p65) is one of the two subunits of NF-κB along with p50, and is closely associated with NF-κB transcriptional activation. The siRelA suppresses RelA, which is closely associated with allergy induction.…”

In Vivo Fluorescence Imaging of Passive Inflammation Site Accumulation of Liposomes via Intravenous Administration Focused on Their Surface Charge and PEG Modification

“…Furthermore, not only antibody drugs that have become mainstream for severe patients, but also antisense oligonucleotides and nucleic acid drugs such as siRNA, miRNA, and aptamer that utilize RNA interference are groundbreaking agents for inflammatory diseases as a novel drug modality [32,43,44]. There are some reports that nanoparticles such as liposomes, polymeric micelles, dendrimers, exosomes, which were loaded these modalities have been intravenously administered, and these improve therapeutic efficacy and attenuate side effects by enhancing active or passive target tissue accumulation [18,[27][28][29][30]37]. However, few studies have comprehensively analyzed what kind of physical property of nanomedicine in the treatment of inflammatory disease by intravenous administration contributes to the accumulation of inflammatory disease and the therapeutic effect.…”

“…We previously reported that intravenous administration of the block-polymer micelle MPEG-PCL-CH2R4H2C and the cytoplasm-sensitive peptide STR-CH2R4H2C had strong therapeutic efficacy against inflammatory diseases such as RA and atopic dermatitis, and cancer [26][27][28][29][30][31][32][33][34][35][36][37]. These molecules were designed in our laboratory as novel drug carriers.…”

Electrostatically Interactive Injectable Hydrogels for Drug Delivery

“…The treatment with chemotherapeutic agents has several disadvantages such as poor distribution to the target tumor sites and several toxic side effects, resulting in the nonspecific distribution to healthy normal tissues. Meanwhile, intratumoral injection of chemotherapeutic agents can achieve a high local concentration of the chemotherapeutic agents at the target tumor site with no or minimal distribution to healthy normal tissues [56][57][58]. The electrostatically interactive in situ-forming hydrogel formulation with chemotherapeutic agents is expected to be easily injected through a syringe needle.…”