Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis (UC), affects millions of patients worldwide.¹ x 1 Khor, B., Gardet, A., and Xavier, R.J. Genetics and pathogenesis of inflammatory bowel disease. Nat Rev. 2011; 474: 307–317 Google Scholar See all References ^{, 2} x 2 Podolsky, D.K. Inflammatory bowel disease. N Engl J Med. 2002; 347: 417–429 Crossref | PubMed | Scopus (2709) | Google Scholar See all References ^{, 3} x 3 Abraham, C. and Cho, H.J. Mechanism of disease inflammatory bowel disease. N Engl J Med. 2009; 361: 2066–2078 Crossref | PubMed | Scopus (1280) | Google Scholar See all References ^{, 4} x 4 Loftus, E.V. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004; 126: 1504–1517 Abstract | Full Text | Full Text PDF | PubMed | Scopus (1847) | Google Scholar See all References Because the etiology and pathogenesis of IBD are not well understood, it is considered an intractable disease. The intestinal mucosa of patients with IBD is characterized by reactive oxygen species (ROS) overproduction and an imbalance of important antioxidants, leading to oxidative damage. Self-sustaining cycles of oxidant production may amplify inflammation and mucosal injury.⁵ x 5 Simmonds, N.J. and Rampton, D.S. Inflammatory bowel disease a radical view. Gut. 1993; 34: 865–868 Crossref | PubMed | Scopus (145) | Google Scholar See all References ^{, 6} x 6 Xavier, R.J. and Podolsky, D.K. Unravelling the pathogenesis of inflammatory bowel disease. Nat Rev. 2007; 448: 427–434 Google Scholar See all References ^{, 7} x 7 Babbs, C.F. Oxygen radicals in ulcerative colitis. Free Radic Biol Med. 1992; 13: 169–182 Crossref | PubMed | Scopus (238) | Google Scholar See all References ^{, 8} x 8 McCord, J.M. The evolution of free radicals and oxidative stress. Am J Med. 2000; 108: 652–659 Abstract | Full Text | Full Text PDF | PubMed | Scopus (790) | Google Scholar See all References In several experimental models, antioxidant compounds and free radical scavengers have improved colitis.⁹ x 9 Jin, Y., Kotakadi, V.S., Ying, L. et al. American ginseng suppresses inflammation and DNA damage associated with mouse colitis. Carcinogenesis. 2008; 29: 2351–2359 Crossref | PubMed | Scopus (44) | Google Scholar See all References ^{, 10} x 10 Ju, J., Hao, X., Lee, M.J. et al. A γ-tocopherol-rich mixture of tocopherols inhibits colon inflammation and carcinogenesis in azoxymethane and dextran sulfate sodium-treated mice. Cancer Prev Re. 2009; 2: 143–152 Crossref | PubMed | Scopus (61) | Google Scholar See all References ^{, 11} x 11 Aggarwal, B.B. and Harikumar, K.B. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009; 41: 40–59 Crossref | PubMed | Scopus (793) | Google Scholar See all References However, these compounds are not completely effective due to a nonspecific drug distribution, low retention in the colon, and side effects. If antioxidant compounds are specifically targeted to the diseased sites and effectively scavenge excessive generated ROS, they represent a safe and effective treatment for IBD.

The ultimate objective of nanoparticle-based therapy is to functionalize nanomedicines in a micro-disease environment without any side effects. Here, we reveal that our pH-responsive nitroxide radical-containing nanoparticles (RNP(pH)) disintegrate within the renal acidic lesion and act as scavengers of reactive oxygen species (ROS), leading to a relief of acute kidney injury (AKI). RNP(pH) was prepared using amphiphilic block copolymers possessing 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) moieties via amine linkage as a side chain of the hydrophobic segment. The self-assembled RNP(pH) disintegrated at pH below 7.0 because of a protonation of the amino groups in the hydrophobic core of the nanoparticles, thereby resulting in an improvement in ROS scavenging activity. Using a renal ischemia-reperfusion AKI model in mice, the therapeutic effect of RNP(pH) on ROS damage was evaluated. Unlike the RNP without pH-triggered disintegration (RNP(Non-pH)), the RNP(pH) showed extremely high ROS scavenging activity and renal protective effects. It is interesting to note that the side effect of nitroxide radicals was markedly suppressed due to the compartmentalization of nitroxide radicals in the core of RNP(pH) in untargeted area. The morphology changes in RNP(pH) were confirmed by analyzing electron spin resonance spectra, and these findings provide the evidence of the real therapeutic effect of the environment-sensitive specific disintegration of nanoparticles in vivo.