Oral Delivery of miR146a Conjugated to Cerium Oxide Nanoparticles Improves an Established T Cell-Mediated Experimental Colitis in Mice
Anisha Apte,
Pujarini Dutta Dey,
Srisaianirudh Reddy Julakanti,
Monica Midura-Kiela,
Stacy M. Skopp,
Jimena Canchis,
Tobias Fauser,
James Bardill,
Sudipta Seal,
David M. Jackson,
Fayez K. Ghishan,
Pawel R. Kiela,
Carlos Zgheib,
Kenneth W. Liechty
Affiliations
Anisha Apte
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
Pujarini Dutta Dey
Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children’s Research Center, University of Arizona Health Sciences Center, Tucson, AZ 85621, USA
Srisaianirudh Reddy Julakanti
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
Monica Midura-Kiela
Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children’s Research Center, University of Arizona Health Sciences Center, Tucson, AZ 85621, USA
Stacy M. Skopp
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
Jimena Canchis
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
Tobias Fauser
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
James Bardill
Laboratory for Fetal and Regenerative Biology, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO 80045, USA
Sudipta Seal
Advanced Materials Processing and Analysis Center, Nanoscience Technology Center, University of Central Florida, Orlando, FL 32826, USA
David M. Jackson
Ceria Therapeutics, Inc., Tucson, AZ 85721, USA
Fayez K. Ghishan
Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children’s Research Center, University of Arizona Health Sciences Center, Tucson, AZ 85621, USA
Pawel R. Kiela
Department of Pediatrics, Daniel Cracchiolo Institute for Pediatric Autoimmune Disease Research, Steele Children’s Research Center, University of Arizona Health Sciences Center, Tucson, AZ 85621, USA
Carlos Zgheib
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
Kenneth W. Liechty
Laboratory for Fetal and Regenerative Biology, Department of Surgery, University of Arizona Tucson College of Medicine, Banner Children’s at Diamond Children’s Medical Center, 1656 E Mabel St, Rm 230, Tucson, AZ 85721, USA
Background: Dysregulated inflammation and oxidative stress are strongly implicated in the pathogenesis of inflammatory bowel disease. We have developed a novel therapeutic that targets inflammation and oxidative stress. It is comprised of microRNA-146a (miR146a)-loaded cerium oxide nanoparticles (CNPs) (CNP-miR146a). We hypothesized that oral delivery of CNP-miR146a would reduce colonic inflammation in a mouse model of established, chronic, T cell-mediated colitis. Methods: The stability of CNP-miR146a and mucosal delivery was assessed in vitro with simulated gastrointestinal fluid and in vivo after oral gavage by quantitative real-time RT-PCR. The efficacy of orally administered CNP-miR146a was tested in mice with established colitis using the model of adoptive naïve T-cell transfer in recombinant activating gene 2 knockout (Rag2−/−) mice. Measured outcomes included histopathology; CD45+ immune cell infiltration; oxidative DNA damage (tissue 8-hydroxy-2′-deoxyguanosine; 8-OHdG); expression of IL-6 and TNF mRNA and protein, and flow cytometry analysis of lamina propria Th1 and Th17 cell populations. Results: miR146a expression remained stable in simulated gastric and intestinal conditions. miR146a expression increased in the intestines of mice six hours following oral gavage of CNP-miR146a. Oral delivery of CNP-miR146a in mice with colitis was associated with reduced inflammation and oxidative stress in the proximal and distal colons as evidenced by histopathology scoring, reduced immune cell infiltration, reduced IL-6 and TNF expression, and decreased populations of CD4+Tbet+IFNg+ Th1, CD4+RorgT+IL17+ Th17, as well as pathogenic double positive IFNg+IL17+ T cells. Conclusions: CNP-miR146a represents a novel orally available therapeutic with high potential to advance into clinical trials.
