An orally administered redox nanoparticle that accumulates in the colonic mucosa and reduces colitis in mice

BACKGROUND & AIMS: Drugs used to treat patients with ulcerative colitis are not always effective because of nonspecific distribution, metabolism in the gastrointestinal tract, and side effects. We designed a nitroxide radical-containing nanoparticle (RNP^O) that accumulates specifically in the colon to suppress inflammation and reduce the undesirable side effects of nitroxide radicals. METHODS: RNP^O was synthesized by assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in an ether-linked hydrophobic side chain. Biodistribution of RNP^O in mice was determined from radioisotope and electron spin resonance measurements. The effects of RNP^O were determined in mice with dextran sodium sulfate (DSS)-induced colitis and compared with those of low-molecular-weight drugs (4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl [TEMPOL] or mesalamine). RESULTS: RNP^O, with a diameter of 40 nm and a shell of poly(ethylene glycol), had a significantly greater level of accumulation in the colonic mucosa than low-molecular-weight TEMPOL or polystyrene latex particles. RNP ^O was not absorbed into the bloodstream through the intestinal wall, despite its long-term retention in the colon, which prevented its distribution to other parts of the body. Mice with DSS-induced colitis had significantly lower disease activity index and less inflammation following 7 days of oral administration of RNP^O compared with mice with DSS-induced colitis or mice given low-molecular-weight TEMPOL or mesalamine. CONCLUSIONS: We designed an orally administered RNP^O that accumulates specifically in the colons of mice with colitis and is more effective in reducing inflammation than low-molecular-weight TEMPOL or mesalamine. RNP^O might be developed for treatment of patients with ulcerative colitis.