An Orally Administered Redox Nanoparticle That Accumulates in the Colonic Mucosa and Reduces Colitis in Mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 143; no. 4; pp. 1027 - 1036.e3
• Main Authors: Vong, Long Binh, Tomita, Tsutomu, Yoshitomi, Toru, Matsui, Hirofumi, Nagasaki, Yukio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2012
• Subjects: Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Antioxidants - pharmacokinetics; Antioxidants - therapeutic use; Colitis - chemically induced; Colitis - drug therapy; Colitis - metabolism; Colon - enzymology; Colon - metabolism; Cyclic N-Oxides - pharmacokinetics; Cyclic N-Oxides - therapeutic use; Dextran Sulfate; Gastroenterology and Hepatology; Inflammatory Bowel Disease; Interleukin-1beta - metabolism; Intestinal Mucosa - enzymology; Intestinal Mucosa - metabolism; Male; Mesalamine - therapeutic use; Mice; Mice, Inbred ICR; Nanoparticles - therapeutic use; Nanotherapy; Nitrogen Oxides - blood; Nitrogen Oxides - pharmacokinetics; Nitrogen Oxides - therapeutic use; Nitroxide Radical-Containing Nanoparticles; Peroxidase - metabolism; Reactive Oxygen Species; Reactive Oxygen Species - antagonists & inhibitors; Severity of Illness Index; Spin Labels; Superoxides - metabolism; Survival Rate; Reactive Oxygen Species; nitroxide radical-containing nanoparticles prepared by poly(ethylene glycol)- b-poly(4-[2,2,6,6-tetramethylpiperidine-1-oxyl]aminomethylstyrene); nitroxide radical-containing nanoparticles prepared by methoxy-poly(ethylene glycol)- b-poly(4-[2,2,6,6-tetramethylpiperidine-1-oxyl]oxymethylstyrene); MPO; Nanotherapy; electron spin resonance; Inflammatory Bowel Disease; interleukin; 4-hydroxyl-2,2,6,6-tetramethylpiperidine-1-oxyl; MeO-PEG- b-PMOT; IL; DSS; ESR; dextran sodium sulfate; myeloperoxidase; RNP N; RNP O; DAI; MeO-PEG- b-PCMS; TEMPOL; disease activity index; ROS; methoxy-poly(ethylene glycol)- b-poly(4-[2,2,6,6-tetramethylpiperidine-1-oxyl]oxymethylstyrene); Nitroxide Radical-Containing Nanoparticles; methoxy-poly(ethylene glycol)- b-poly(chloromethylstyrene); MeO-PEG-b-PMOT; MeO-PEG-b-PCMS; RNPN; RNPO
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2012.06.043

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 (RNPO ) that accumulates specifically in the colon to suppress inflammation and reduce the undesirable side effects of nitroxide radicals. Methods RNPO was synthesized by assembly of an amphiphilic block copolymer that contains stable nitroxide radicals in an ether-linked hydrophobic side chain. Biodistribution of RNPO in mice was determined from radioisotope and electron spin resonance measurements. The effects of RNPO 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 RNPO , 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. RNPO 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 RNPO compared with mice with DSS-induced colitis or mice given low-molecular-weight TEMPOL or mesalamine. Conclusions We designed an orally administered RNPO that accumulates specifically in the colons of mice with colitis and is more effective in reducing inflammation than low-molecular-weight TEMPOL or mesalamine. RNPO might be developed for treatment of patients with ulcerative colitis.