- 著者
- Sha Sha Vong Long Binh Chonpathompikunlert Pennapa Yoshitomi Toru Matsui Hirofumi Nagasaki Yukio
- 出版者
- Elsevier
- 雑誌
- Biomaterials (ISSN:01429612)
- 巻号頁・発行日
- vol.34, no.33, pp.8393-8400, 2013-11
- 被引用文献数
- 47 5
Patients regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (IND) have a risk of small intestinal injuries. In this study, we have developed an oral nanotherapeutics by using a redox nanoparticle (RNPO), which is prepared by self-assembly of an amphiphilic block copolymer that possesses nitroxide radicals as side chains of hydrophobic segment via ether linkage, to reduce inflammation in mice with IND-induced small intestinal injury. The localization and accumulation of RNPO in the small intestine were determined using fluorescent-labeled RNPO and electron spin resonance. After oral administration, the accumulation of RNPO in both the jejunum and ileum tissues was about 40 times higher than those of low-molecular-weight nitroxide radical compounds, and RNPO was not absorbed into the bloodstream via the mesentery, thereby avoiding the adverse effects of nitroxide radicals in the entire body. RNPO remarkably suppressed inflammatory mediators such as myeloperoxidase, superoxide anion, and malondialdehyde in the small intestines of IND-treated mice. Compared to low-molecular-weight nitroxide radical compounds, RNPO also significantly increased the survival rate of mice treated daily with IND. On the basis of these results, RNPO is promising as a nanotherapeutics for treatment of inflammation in the small intestine of patients receiving NSAIDs.
- 著者
- Toh Kazuko Yoshitomi Toru Ikeda Yutaka Nagasaki Yukio
- 出版者
- IOP PUBLISHING
- 雑誌
- Science and technology of advanced materials (ISSN:14686996)
- 巻号頁・発行日
- vol.12, no.6, pp.065001, 2011
- 被引用文献数
- 8
Gene therapy has generated worldwide attention as a new medical technology. While non-viral gene vectors are promising candidates as gene carriers, they have several issues such as toxicity and low transfection efficiency. We have hypothesized that the generation of reactive oxygen species (ROS) affects gene expression in polyplex supported gene delivery systems. The effect of ROS on the gene expression of polyplex was evaluated using a nitroxide radical-containing nanoparticle (RNP) as an ROS scavenger. When polyethyleneimine (PEI)/pGL3 or PEI alone was added to the HeLa cells, ROS levels increased significantly. In contrast, when (PEI)/pGL3 or PEI was added with RNP, the ROS levels were suppressed. The luciferase expression was increased by the treatment with RNP in a dose-dependent manner and the cellular uptake of pDNA was also increased. Inflammatory cytokines play an important role in ROS generation in vivo. In particular, tumor necrosis factor (TNF)-α caused intracellular ROS generation in HeLa cells and decreased gene expression. RNP treatment suppressed ROS production even in the presence of TNF-α and increased gene expression. This anti-inflammatory property of RNP suggests that it may be used as an effective adjuvant for non-viral gene delivery systems.
- 著者
- Vong Long Binh Tomita Tsutomu Yoshitomi Toru Matsui Hirofumi Nagasaki Yukio
- 出版者
- Elsevier
- 雑誌
- Gastroenterology (ISSN:00165085)
- 巻号頁・発行日
- vol.143, no.4, pp.1027-1036.e3, 2012-10
- 被引用文献数
- 155 22
Background & AimsDrugs 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.MethodsRNPO 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).ResultsRNPO, 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.ConclusionsWe 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.