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

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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

Hossain Md. Amran Ikeda Yutaka Hara Toru Nagasaki Yukio

出版者

Elsevier

雑誌

Colloids and surfaces. B, Biointerfaces (ISSN:09277765)

巻号頁・発行日

vol.102, pp.778-782, 2013-02

被引用文献数

7 3

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A new approach to the preparation of PEGylated [PEG: poly(ethylene glycol)] SiO2/Au hybrid nanoparticles was investigated. The synthesis of a PEGylated nanogel containing SiO2/Au hybrid nanoparticles was performed using matrix-catalyzed hydrolysis of tetraethyl orthosilicate, followed by the reduction of HAuCl4. UV–vis absorption of the prepared hybrid particles was obtained at 618 nm, which is a much longer wavelength than that of a nanogel containing only Au nanoparticles (523 nm). High-angle annular dark field images of the prepared particles observed using transmission electron microscopy and energy-dispersive X-ray spectroscopy confirmed the coexistence of Si and Au in the same particle. The presence of Si and Au in the prepared particles was also confirmed by inductively coupled plasma atomic emission spectroscopy. Dynamic light-scattering measurements of the particles in a highly ionic medium showed that they have high stability in both acidic and basic regions.

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

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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

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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.

著者

Yuan Xiaofei Fabregat Dolça Yoshimoto Keitaro Nagasaki Yukio

出版者

Elsevier

雑誌

Colloids and surfaces. B, Biointerfaces (ISSN:09277765)

巻号頁・発行日

vol.99, pp.45-52, 2012-11

被引用文献数

23

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Rabbit anti-human ferritin (anti-hFT) polyclonal immunoglobulin G (IgG) and poly(ethylene glycol) (PEG) were sequentially co-immobilized onto polystyrene submicroparticles (sMPs) to construct sMP/anti-hFT/PEG (SAP) immunolatex. Chemical immobilization of anti-hFT was performed at different pH levels to evaluate variations in antigen recognition. Basic pH disfavored conjugation of anti-hFT to sMPs, but remarkably increased its antigen recognition in comparison to that at neutral pH. We investigated this intriguing phenomenon further by assessing the kinetics of antibody binding, including the time-dependency of immobilization, antigen recognition, and orientation of bound anti-hFT. Therefore, we attributed high antigen recognition to significant electrostatic repulsion between sMPs and anti-hFT at basic pH, which predominately prevented anti-hFT access to sMPs and concurrently promoted anti-hFT orientations suitable for antigen recognition. Subsequent PEG modification maintained such anti-hFT orientation, without which antigen-accessible orientations would have decreased with time. Thus, properly oriented antibody and immediate PEGylation after antibody immobilization contributed to the formation of a high-performance SAP immunolatex.