PROJECT SUMMARY/ABSTRACT The principal goals of this project are to develop a novel computed tomography (CT) contrast agent, i.e., dextran coated cerium oxide nanoparticles (Dex-CeNP) to image the gastrointestinal tract (GIT) of those afflicted with inflammatory bowel disease (IBD) and that can also be used to treat and improve the quality of life of people with IBD. Iodine and barium-based contrast agents are currently used in the clinic for GIT imaging with CT. However, these contrast agents are not specific for inflammation sites, limiting their diagnostic utility for IBD imaging. Thus, there is a compelling need to develop novel CT contrast agents for this application. Cerium is a potential element to use for novel contrast agents due to its strong CT contrast generation. Despite this, cerium contrast agents have rarely been investigated for CT imaging. Aside from the excellent x-ray contrast, cerium possesses important properties for the treatment of IBD. Current management of IBD relies on nonspecific immunosuppressive therapies (such as steroids), antibiotics, and biologically targeting the pro-inflammatory tumor necrosis factor pathway. However, these treatments are not effective in all patients and have significant limitations, as the effects of these treatments are not long term. Several studies have highlighted the role of oxidative stress in IBD. The increased production of reactive oxygen species (ROS) in combination with reduced total antioxidant capacity results in considerable oxidative stress in the chronically inflamed colon mucosa of IBD. Recent studies have suggested that antioxidant administration may be beneficial in the treatment of IBD. Cerium oxide nanoparticles have been proposed as an artificial antioxidant as they neutralize free radicals, therefore they may reduce symptoms in patients with IBD. Dextran coating will be used to provide nanoparticle stability, while maintaining catalytic activity and encouraging targeting to sites of inflammation. This proposal will test the hypotheses that Dex-CeNP will accumulate in IBD inflammation sites to allow their detection with CT and that they can be beneficial to patients with IBD due to their antioxidant properties. The proposed research will provide an opportunity for the applicant to acquire skills in the areas of nanoparticle synthesis, CT imaging and treatment of IBD. Training and support for the project will be provided by a multi-disciplinary mentoring team. The pursuit of this work will advance the diagnostic and treatment options for IBD, as well as provide a rich training experience that will position the applicant for future success.

PROJECT NARRATIVE Medical imaging of inflammatory bowel disease is challenging since current contrast agents are not specific for sites of inflammation. In addition, new drugs are needed to treat the undesirable effects of inflammatory bowel disease. This proposal explores the synthesis and testing of a novel contrast agent, dextran-coated cerium oxide nanoparticles (Dex-CeNP) to simultaneously image and treat inflammatory bowel disease.