Digestive Diseases News Summer 2011
Nanoparticles Deliver IBD Treatment Straight to the Gut
Scientists funded by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) have potentially developed a safer, more effective, and more convenient way to treat inflammatory bowel disease (IBD), a group of conditions that causes painful ulcers of the gastrointestinal (GI) tract. In experiments with mice, thioketal nanoparticles (TKNs) specifically targeted inflamed tissues of the GI tract while protecting their therapeutic payload from digestion. When coated with TKNs, anti-tumor necrosis factor-α (TNF-α) small interfering RNA (siRNA) effectively protected mice from dextran sodium sulfate (DSS)-induced colitis.
“Using a murine model of ulcerative colitis, we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine TNF-α diminish TNF-α messenger RNA levels in the colon and protect mice from ulcerative colitis,” wrote Niren Murthy, Ph.D., of Georgia Tech’s Wallace H. Coulter Department of Biomedical Engineering, and co-authors in the November 2010 issue of Nature Materials.
Crohn’s disease and ulcerative colitis are the two major forms of IBD. Both are caused by the body’s own immune cells attacking the intestinal epithelium. Whereas Crohn’s disease affects any part of the GI tract, ulcerative colitis usually only affects the large intestine. Both conditions can cause chronic, painful, and sometimes bloody diarrhea. About 1.4 million Americans have Crohn’s disease or ulcerative colitis.
The anti-TNF-α biologics infliximab (Remicade) and adalimumab (Humira) consist of antibody proteins that bind and halt the action of the proinflammatory cytokine TNF-α. Inflammatory cytokines are biochemical messengers made by the body that mediate the immune response to infection. In people with IBD, halting TNF-α interrupts the inflammatory pathway that leads to intestinal ulcers.
Anti-TNF-α biologics have dramatically improved the lives of many people with IBD but are unstable in the GI tract and, therefore, must be administered intravenously or by subcutaneous injection. More than painful and inconvenient, intravenous and subcutaneous administration means systemic exposure to these potent biologics, increasing the risk of serious side effects.
The therapeutic strategy developed by Murthy and co-authors takes advantage of a relatively new technology called siRNA to decrease TNF-α production. siRNA bind cells’ RNA, the biochemical intermediary between DNA and functional proteins, to suppress gene function. TNF-α siRNA specifically target TNF-α RNA, preventing TNF-α protein production and thus interrupting the inflammatory pathway that leads to intestinal ulcers. Like protein-based anti-TNF-α biologics, siRNA also breaks down in the GI system. However, because of its smaller size, siRNA is easier to coat with nanoparticles.
The researchers developed TKNs, polymers composed of thioketal linkages, to protect TNF-α siRNA and specifically target inflamed intestinal tissues. Thioketal linkages are resistant to the digestive enzymes and the acidic environment of the GI tract; however, they degrade when exposed to reactive oxygen species (ROS), a substance released by inflamed tissues. “At sites of intestinal inflammation, the elevated ROS levels trigger the degradation of the TNF-α TKNs, thus localizing the release of siRNA to inflamed intestinal tissues,” wrote Murthy and co-authors.
When coated with TKNs, TNF-α siRNA effectively protected mice from DSS-induced colitis. Mice given DSS for 7 days developed bowel ulcers similar to ulcers seen in people with IBD. However, mice given TNF-α TKNs alongside DSS were free of ulcers, had normal-looking intestinal epitheliums, and were significantly heavier compared with controls. Intestinal tissues from mice that received TNF-α TKNs also had lower levels of myeloperoxidase, a proinflammatory enzyme released by immune cells.
“On the basis of our results, we expect that TKNs will make a significant contribution to the treatment of numerous gastrointestinal diseases linked to intestinal inflammation, including GI cancers, inflammatory bowel diseases, and viral infections,” wrote Murthy and co-authors.
The National Digestive Diseases Information Clearinghouse, an information service of the NIDDK, has free fact sheets and easy-to-read booklets about IBD. For more information or to obtain copies, visit www.digestive.niddk.nih.gov.
For more information about nanotechnology, visit www.nih.gov/science/nanotechnology.
NIH Publication No. 11–4552