Nanoparticles With Surface Antibody Against CD98 and Carrying CD98 Small Interfering RNA Reduce Colitis in Mice

• Type of Material: Article
• Authors: Bo Laroui, Georgia State University; Hamed Viennois, Georgia State University; Emilie Ayyadurai, Georgia State University; Saravanan Charania, Georgia State University; Moiz A. Zhang, Georgia State University; Yuchen Zhang, Georgia State University; Zhan Baker, Georgia State University; Mark T. Zhang, Georgia State University; Andrew Gewirtz, Emory University; Bo Xiao, Georgia State University; Didier Merlin, Georgia State University
• Language: English
• Date: 2014-05-01
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1053/j.gastro.2014.01.056
• Title of Journal or Parent Work: Gastroenterology
• ISSN: 0016-5085
• Volume: 146
• Issue: 5
• Start Page: 1289
• End Page: +
• Grant/Funding Information: Supported by grants from the Department of Veterans Affairs; the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases grant RO1-DK-071594 (to D.M); Career Development Award KO1-DK-097192 (to H.L.); and the American Heart Association Postdoctoral Fellowship Grant 13POST16400004 (to B.X.).
• Keywords: CHITOSAN; SIRNA DELIVERY; GENE DELIVERY; Science & Technology; CD98; Mouse Model; Colitis-Targeted Therapy; INFECTION; INTESTINAL EPITHELIAL CD98; Gastroenterology & Hepatology; Gene Silencing; T-CELL RESPONSES; IBD; Life Sciences & Biomedicine; INFLAMMATORY-BOWEL-DISEASE; MACROPHAGE ACTIVATION; PROTEIN
• Research Categories: Health Sciences, Immunology; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Background & Aims: Nanoparticles have been explored as carriers of small interfering RNAs (siRNAs) and might be developed to treat patients with inflammatory bowel disease (IBD). Overexpression of CD98 on the surface of colonic epithelial cells and macrophages promotes the development and progression of IBD. We developed an orally delivered hydrogel that releases nanoparticles with single-chain CD98 antibodies on their surface (scCD98 functionalized) and loaded with CD98 siRNA (siCD98). We tested the ability of the nanoparticles to reduce levels of CD98 in the colons of mice with colitis. Methods: scCD98-functionalized siCD98-loaded nanoparticles were fabricated using a complex coacervation technique. We investigated the cellular uptake and lysosome escape profiles of the nanoparticles in Colon-26 cells and RAW 264.7 macrophages using fluorescence microscopy. Colitis was induced by transfer of CD4+CD45RBhigh T cells to Rag-/- mice or administration of dextran sodium sulfate to C57BL/6 mice. Mice were then given hydrogel (chitosan and alginate) containing scCD98-functionalized nanoparticles loaded with siCD98 or scrambled siRNA (control) via gavage. Results: The scCD98-functionalized nanoparticles were approximately 200 nm in size and had high affinity for CD98-overexpressing cells. The scCD98-functionalized siCD98-loaded nanoparticles significantly reduced levels of CD98 in Colon-26 cells and RAW 264.7 macrophages, along with production of inflammatory cytokines (tumor necrosis factor α, interleukin-6, and interleukin-12). In mice with colitis, administration of the scCD98-functionalized siCD98-loaded nanoparticles reduced colon expression of CD98. Importantly, the severity of colitis was also reduced compared with controls (based on loss of body weight, myeloperoxidase activity, inflammatory cytokine production, and histological analysis). Approximately 24.1% of colonic macrophages (CD11b +CD11c-F4/80+) in the mice had taken up fluorescently labeled siRNA-loaded nanoparticles within 12 hours of administration. Conclusions: Nanoparticles containing surface CD98 antibody and loaded with siCD98 reduce expression of this protein by colonic epithelial cells and macrophages, and oral administration decreases the severity of colitis in mice. This nanoparticle in hydrogel (chitosan/alginate) formulation might be developed to treat patients with IBD.