Orally delivered thioketal nanoparticles loaded with TNF-α–siRNA target inflammation and inhibit gene expression in the intestines
Source abstract
Abstract
Small interfering RNAs (siRNAs) directed against proinflammatory cytokines have the potential to treat numerous diseases associated with intestinal inflammation; however, the side-effects caused by the systemic depletion of cytokines demands that the delivery of cytokine-targeted siRNAs be localized to diseased intestinal tissues. Although various delivery vehicles have been developed to orally deliver therapeutics to intestinal tissue, none of these strategies has demonstrated the ability to protect siRNA from the harsh environment of the gastrointestinal tract and target its delivery to inflamed intestinal tissue. Here, we present a delivery vehicle for siRNA, termed thioketal nanoparticles (TKNs), that can localize orally delivered siRNA to sites of intestinal inflammation, and thus inhibit gene expression in inflamed intestinal tissue. TKNs are formulated from a polymer, poly-(1,4-phenyleneacetone dimethylene thioketal), that degrades selectively in response to reactive oxygen species (ROS). Therefore, when delivered orally, TKNs release siRNA in response to the abnormally high levels of ROS specific to sites of intestinal inflammation. Using a murine model of ulcerative colitis, we demonstrate that orally administered TKNs loaded with siRNA against the proinflammatory cytokine tumour necrosis factor-alpha (TNF-α) diminish TNF-α messenger RNA levels in the colon and protect mice from ulcerative colitis.
Source: europepmc · Quality: candidate unverified · Source record ↗
Research context
OpenAlex topics: RNA Interference and Gene Delivery · Immunotherapy and Immune Responses · MicroRNA in disease regulation
SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.
References (28)
Show source-provided references
1. Peer, D., Park, E. J., Morishita, Y., Carman, C. V. & Shimaoka, M. Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target. Science 319, 627–630 (2008).10.1126/science.1149859 ↗
2. Wolfe, F., Michaud, K., Anderson, J. & Urbansky, K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 50, 372–379 (2004).10.1002/art.20009 ↗
3. Reddy, J. G. & Loftus, E. V. Jr Safety of infliximab and other biologic agents in the inflammatory bowel diseases. Gastroenterol Clin. North Am. 35, 837–855 (2006).10.1016/j.gtc.2006.09.008 ↗
4. Heraganahally, S. S. et al. Pulmonary toxicity associated with infliximab therapy for ulcerative colitis. Int. Med. J. 39, 629–630 (2009).10.1111/j.1445-5994.2009.001999.x ↗
5. Aouadi, M. et al. Orally delivered siRNA targeting macrophage Map4k4 suppresses systemic inflammation. Nature 458, 1180–1184 (2009).10.1038/nature07774 ↗
6. Pertuit, D. et al. 5-amino salicylic acid bound nanoparticles for the therapy of inflammatory bowel disease. J. Control. Release. 123, 211–218 (2007).10.1016/j.jconrel.2007.08.008 ↗
7. Yamanaka, Y. J. & Leong, K. W. Engineering strategies to enhance nanoparticle-mediated oral delivery. J. Biomater. Sci. Polym. Ed. 19, 1549–1570 (2008).10.1163/156856208786440479 ↗
8. Lih-Brody, L. et al. Increased oxidative stress and decreased antioxidant defenses in mucosa of inflammatory bowel disease. Dig. Dis. Sci. 41, 2078–2086 (1996).10.1007/BF02093613 ↗
9. Kountouras, J., Chatzopoulos, D. & Zavos, C. Reactive oxygen metabolites and upper gastrointestinal diseases. Hepatogastroenterology 48, 743–751 (2001).
10. Simmonds, N. J. et al. Chemiluminescence assay of mucosal reactive oxygen metabolites in inflammatory bowel disease. Gastroenterology 103, 186–196 (1992).10.1016/0016-5085(92)91112-H ↗
11. Sedghi, S. et al. Increased production of luminol enhanced chemiluminescence by the inflamed colonic mucosa in patients with ulcerative colitis. Gut 34, 1191–1197 (1993).10.1136/gut.34.9.1191 ↗
12. Peng, Y. C. et al. Chemiluminescence assay of mucosal reactive oxygen species in gastric cancer, ulcer and antral mucosa. Hepatogastroenterology 55, 770–773 (2008).
13. Shukla, A. K., Verma, M. & Singh, K. N. Superoxide induced deprotection of 1,3-dithiolanes: A convenient method of dedithioacetalization. Indian J. Chem. B 43, 1748–1752 (2004).
14. Colonna, S., Gaggero, N., Carrea, G. & Pasta, P. Enantio and diastereoselectivity of cyclohexanone monooxygenase catalyzed oxidation of 1,3-dithioacetals. Tetrahedron-Asymmetr. 7, 565–570 (1996).10.1016/0957-4166(96)00040-7 ↗
15. Mahida, Y. R., Wu, K. C. & Jewell, D. P. Respiratory burst activity of intestinal macrophages in normal and inflammatory bowel-disease. Gut 30, 1362–1370 (1989).10.1136/gut.30.10.1362 ↗
16. Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: Implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).10.1016/S1074-7613(00)80038-2 ↗
17. Sorensen, D. R., Leirdal, M. & Sioud, M. Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J. Mol. Biol. 327, 761–766 (2003).10.1016/S0022-2836(03)00181-5 ↗
18. Leirdal, M. & Sioud, M. Gene silencing in mammalian cells by preformed small RNA duplexes. Biochem. Biophys. Res. Commun. 295, 744–748 (2002).10.1016/S0006-291X(02)00736-2 ↗
19. Murata, N., Takashima, Y., Toyoshima, K., Yamamoto, M. & Okada, H. Anti-tumour effects of anti-VEGF siRNA encapsulated with PLGA microspheres in mice. J. Control. Release. 126, 246–254 (2008).10.1016/j.jconrel.2007.11.017 ↗
20. Palliser, D. et al. An siRNA-based microbicide protects mice from lethal herpes simplex virus 2 infection. Nature 439, 89–94 (2006).10.1038/nature04263 ↗
21. Akhtar, S. & Benter, I. F. Nonviral delivery of synthetic siRNAs in vivo. J. Clin. Invest. 117, 3623–3632 (2007).10.1172/JCI33494 ↗
22. Zhang, S., Zhao, B., Jiang, H., Wang, B. & Ma, B. Cationic lipids and polymers mediated vectors for delivery of siRNA. J. Control. Release. 123, 1–10 (2007).10.1016/j.jconrel.2007.07.016 ↗
23. Thiele, L. et al. Evaluation of particle uptake in human blood monocyte-derived cells in vitro. Does phagocytosis activity of dendritic cells measure up with macrophages? J. Control. Release. 76, 59–71 (2001).10.1016/S0168-3659(01)00412-6 ↗
24. Hariharan, S. et al. Design of estradiol loaded PLGA nanoparticulate formulations: A potential oral delivery system for hormone therapy. Pharm. Res. 23, 184–195 (2006).10.1007/s11095-005-8418-y ↗
25. Desai, M. P., Labhasetwar, V., Amidon, G. L. & Levy, R. J. Gastrointestinal uptake of biodegradable microparticles: Effect of particle size. Pharm. Res. 13, 1838–1845 (1996).10.1023/A:1016085108889 ↗
26. Lamprecht, A., Schafer, U. & Lehr, C. M. Size-dependent bioadhesion of micro- and nanoparticulate carriers to the inflamed colonic mucosa. Pharm. Res. 18, 788–793 (2001).10.1023/A:1011032328064 ↗
27. Yan, Y. et al. Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulphate induced colitis. PLoS One 4, e6073 (2009).10.1371/journal.pone.0006073 ↗
28. Wirtz, S., Neufert, C., Weigmann, B. & Neurath, M. F. Chemically induced mouse models of intestinal inflammation. Nature Protoc. 2, 541–546 (2007).10.1038/nprot.2007.41 ↗