Nagoya-shi, Japan
Nagoya-shi, Japan

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Oishi K.,Nagoya University | Miyamoto Y.,Nagoya University | Saito H.,MEITO Sangyo Co. | Murase K.,MEITO Sangyo Co. | And 8 more authors.
PLoS ONE | Year: 2013

To monitor pancreatic islet transplantation efficiency, reliable noninvasive imaging methods, such as magnetic resonance imaging (MRI) are needed. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially-available magnetic nanoparticles are not efficiently transduced into cells. We herein report the in vivo detection of transplanted islets labeled with a novel cationic nanoparticle that allowed for noninvasive monitoring of islet grafts in diabetic mice in real time. The positively-charged nanoparticles were transduced into a β-cell line, MIN6 cells, and into isolated islets for 1 hr. MRI showed a marked decrease in the signal intensity on T1- and T2-weighted images at the implantation site of the labeled MIN 6 cells or islets in the left kidneys of mice. These data suggest that the novel positively-charged nanoparticle could be useful to detect and monitor islet engraftment, which would greatly aid in the clinical management of islet transplant patients. © 2013 Oishi et al.


Ishihara Y.,Meiji University | Honma T.,Meiji University | Nohara S.,Meito Sangyo Co. | Ito Y.,Meito Sangyo Co.
BMC Medical Imaging | Year: 2013

Background: Molecular imaging using magnetic nanoparticles (MNPs)-magnetic particle imaging (MPI)-has attracted interest for the early diagnosis of cancer and cardiovascular disease. However, because a steep local magnetic field distribution is required to obtain a defined image, sophisticated hardware is required. Therefore, it is desirable to realize excellent image quality even with low-performance hardware. In this study, the spatial resolution of MPI was evaluated using an image reconstruction method based on the correlation information of the magnetization signal in a time domain and by applying MNP samples made from biocompatible ferucarbotran that have adjusted particle diameters.Methods: The magnetization characteristics and particle diameters of four types of MNP samples made from ferucarbotran were evaluated. A numerical analysis based on our proposed method that calculates the image intensity from correlation information between the magnetization signal generated from MNPs and the system function was attempted, and the obtained image quality was compared with that using the prototype in terms of image resolution and image artifacts.Results: MNP samples obtained by adjusting ferucarbotran showed superior properties to conventional ferucarbotran samples, and numerical analysis showed that the same image quality could be obtained using a gradient magnetic field generator with 0.6 times the performance. However, because image blurring was included theoretically by the proposed method, an algorithm will be required to improve performance.Conclusions: MNP samples obtained by adjusting ferucarbotran showed magnetizing properties superior to conventional ferucarbotran samples, and by using such samples, comparable image quality (spatial resolution) could be obtained with a lower gradient magnetic field intensity. © 2013 Ishihara et al.; licensee BioMed Central Ltd.


PubMed | Fukuoka University, Health Science University, Sapporo Medical University, Meito Sangyo Co. and 3 more.
Type: Journal Article | Journal: Journal of dermatological science | Year: 2014

N-propionyl cysteaminylphenol-maleimide-dextran (NPCMD) is a toxic tyrosinase substrate developed to treat melanoma.We investigated the effect of NPCMD on innate immune responses in monocytes.CD14 monocytes and a monocytic cell line, THP-1, were stimulated with NPCMD in vitro. Cytokines in the culture supernatants were determined by ELISA and flow cytometry.NPCMD stimulated CD14 monocytes and THP-1 cells to secrete TNF, IL-6 and IL-8, but not IL-10 or IL-12. TNF secretion from THP-1 cells stimulated with NPCMD was inhibited by addition of an anti-TLR4 mAb in culture. Moreover, NPCMD stimulated production of pro-IL-1 in CD14 monocytes and monocytic cell line THP-1 cells and activated the NLRP3-inflammasome, resulting in production of mature IL-1. Use of ASC and NLRP3-deficient THP-1 cell lines established involvement of the NLRP3 inflammasome in an IL-1 secretion in treatment with NPCMD. Inhibition of IL-1 secretion by an endocytosis inhibitor, cytochalasin B, and a lysosomal enzyme cathepsin B inhibitor, CA-074 Me, suggested the involvement of lysosomal rupture and leakage of cathepsin B into the cytosol in NLRP3 activation by NPCMD.The immunopotentiating effect of NPCMD mediated by TLR4 and NLRP3 inflammasome activation could be useful for eliciting effective adaptive immune responses against melanoma and other tumors.


PubMed | Japan National Institute of Advanced Industrial Science and Technology, Nagoya University, MEITO Sangyo Co. and University of Ryukyus
Type: Journal Article | Journal: PloS one | Year: 2014

Stem cell transplantation has been expected to have various applications for regenerative medicine. However, in order to detect and trace the transplanted stem cells in the body, non-invasive and widely clinically available cell imaging technologies are required. In this paper, we focused on magnetic resonance (MR) imaging technology, and investigated whether the trimethylamino dextran-coated magnetic iron oxide nanoparticle -03 (TMADM-03), which was newly developed by our group, could be used for labeling adipose tissue-derived stem cells (ASCs) as a contrast agent. No cytotoxicity was observed in ASCs transduced with less than 100 g-Fe/mL of TMADM-03 after a one hour transduction time. The transduction efficiency of TMADM-03 into ASCs was about four-fold more efficient than that of the alkali-treated dextran-coated magnetic iron oxide nanoparticle (ATDM), which is a major component of commercially available contrast agents such as ferucarbotran (Resovist), and the level of labeling was maintained for at least two weeks. In addition, the differentiation ability of ASCs labeled with TMADM-03 and their ability to produce cytokines such as hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE2), were confirmed to be maintained. The ASCs labeled with TMADM-03 were transplanted into the left kidney capsule of a mouse. The labeled ASCs could be imaged with good contrast using a 1T MR imaging system. These data suggest that TMADM-03 can therefore be utilized as a contrast agent for the MR imaging of stem cells.


PubMed | Ichikawa General Hospital, MEITO Sangyo Co., Nagoya Kyoritsu Hospital, Chiba East Hospital and 2 more.
Type: Journal Article | Journal: Cell medicine | Year: 2016

Magnetic resonance imaging (MRI) using magnetic nanoparticles has been used to diagnose vascular diseases as well as to monitor transplanted cells and tissues. In this study, we synthesized magnetic iron oxide nanoparticles (TMADM-03), electrically charged by the presence of a cationic end-group substitution of dextran, and observed these nanoparticles inside three-dimensional models of HepG2 spheroids, which mimic tissues. Patterned cell array glass disks were prepared to visualize the presence of TMADM-03 uptaken by HepG2 spheroids using transmission electron microscopy (TEM). The HepG2 cells (2 10(5) cells) were inoculated onto Cell-able 12-well plates. After 48 h of culture, the cells were incubated with 75 g Fe/ml TMADM-03 in culture medium for 24 h. To investigate the cellular function of the HepG2 spheroids, the albumin secretion was evaluated by an ELISA. The albumin secretion after incubation for 24 h was reduced compared with the secretion prior to the addition of TMADM-03. TEM image samples were prepared in a planar direction or a vertical direction to the HepG2 spheroids on patterned cell array glass disks. The incorporation of TMADM-03 inside the HepG2 spheroids was confirmed. In addition, TMADM-03 could be observed in the deeper layers of the spheroids, and this was localized in the lysosomes. These data suggest that the novel magnetic iron oxide nanoparticles invade three-dimensional HepG2 spheroids.


Tsuchiya K.,Shiga University of Medical Science | Nitta N.,Shiga University of Medical Science | Sonoda A.,Shiga University of Medical Science | Otani H.,Shiga University of Medical Science | And 5 more authors.
European Journal of Radiology | Year: 2013

Purpose We used magnetic resonance imaging (MRI) and histologic techniques to compare the uptake by the rabbit atherosclerotic wall of 4 types of superparamagnetic iron oxide (SPIO) particles, i.e. SPIO, mannan-coated SPIO (M-SPIO), ultrasmall SPIO (USPIO), and mannan-coated USPIO (M-USPIO). Materials and methods All experimental protocols were approved by our institutional animal experimentation committee. We intravenously injected 12 Watanabe heritable hyperlipidemic rabbits with one of the 4 types of SPIO (0.8 mmol Fe/kg). Two other rabbits served as the control. The rabbits underwent in vivo contrast-enhanced magnetic resonance angiography (MRA) before- and 5 days after these injections; excised aortae were subjected to in vitro MRI. In the in vivo and in vitro studies we assessed the signal intensity of the vessels at identical regions of interest (ROI) and calculated the signal-to-noise ratio (SNR). For histologic assessment we evaluated the iron-positive regions in Prussian blue-stained specimens. Results There were significant differences in iron-positive regions where M-USPIO > USPIO, M-SPIO > SPIO, USPIO > SPIO (p < 0.05) but not between M-USPIO and M-SPIO. The difference between the pre- and post-injection SNR was significantly greater in rabbits treated with M-USPIO than USPIO and in rabbits injected with M-SPIO than SPIO (p < 0.05). On in vitro MRI scans SNR tended to be lower in M-USPIO- and M-SPIO- than USPIO- and SPIO-treated rabbits (p < 0.1). Conclusion Histologic and imaging analysis showed that mannan-coated SPIO and USPIO particles were taken up more readily by the atherosclerotic rabbit wall than uncoated SPIO and USPIO. © 2013 Elsevier Ireland Ltd. All rights reserved.


Saito S.,Health Science University | Tsugeno M.,Health Science University | Koto D.,Health Science University | Mori Y.,Osaka University | And 3 more authors.
International Journal of Nanomedicine | Year: 2012

Purpose: Magnetic resonance imaging (MRI) using contrast agents like superparamagnetic iron oxide (SPIO) is an extremely versatile technique to diagnose diseases and to monitor treatment. This study tested the relative importance of particle size and surface coating for the optimization of MRI contrast and labeling efficiency of macrophages migrating to remote inflammation sites. Materials and methods: We tested four SPIO and ultrasmall superparamagnetic iron oxide (USPIO), alkali-treated dextran magnetite (ATDM) with particle sizes of 28 and 74 nm, and carboxymethyl dextran magnetite (CMDM) with particle sizes of 28 and 72 nm. Mouse macrophage RAW264 cells were incubated with SPIOs and USPIOs, and the labeling efficiency of the cells was determined by the percentage of Berlin blue-stained cells and by measuring T2 relaxation times with 11.7-T MRI. We used trypan blue staining to measure cell viability. Results: Analysis of the properties of the nanoparticles revealed that ATDM-coated 74 nm particles have a lower T2 relaxation time than the others, translating into a higher ability of MRI negative contrast agent. Among the other three candidates, CMDM-coated particles showed the highest T2 relaxation time once internalized by macrophages. Regarding labeling efficiency, ATDM coating resulted in a cellular uptake higher than CMDM coating, independent of nanoparticle size. None of these particle formulations affected macrophage viability. Conclusion: This study suggests that coating is more critical than size to optimize the SPIO labeling of macrophages. Among the formulations tested in this study, the best MRI contrast and labeling efficiency are expected with ATDM-coated 74 nm nanoparticles. © 2012 Cárdenas et al, publisher and licensee Dove Medical Press Ltd.


Oishi K.,Nagoya University | Noguchi H.,Nagoya University | Noguchi H.,Baylor Research Institute | Saito H.,MEITO Sangyo Co. | And 4 more authors.
Cell Transplantation | Year: 2010

Cell therapy is a proven and efficient method for treating multiple diseases. For both basic research and clinical practice, the development of noninvasive in vivo imaging methods is essential for monitoring the trafficking or homing of transplanted cells. One attractive approach for the effective imaging of transplanted cells is the efficient labeling of cells with a contrast agent. In this study, we developed a novel contrast agent of magnetic resonance imaging (MRI), TMADM-02. TMADM-02 was efficiently transduced into cells without toxicity. However, the aggregation of TMADM-02 was observed because of its low stability in culture medium. Therefore, TMADM-02 may have led to a false-positive test result. In future studies, we should verify not only the efficiency of labeling cells but also the stability of the contrast agent of MRI for clinical applications. Copyright © 2010 Cognizant Comm. Corp.


PubMed | Nagoya University and MEITO Sangyo Co.
Type: Journal Article | Journal: Cell medicine | Year: 2017

Significant graft loss immediately after islet transplantation occurs due to immunological and nonimmunological events. Magnetic resonance imaging (MRI) is an attractive potential tool for monitoring islet mass in vivo. Although an efficient uptake of MRI contrast agent is required for islet cell labeling, commercially available magnetic nanoparticles are not efficiently transduced into cells. In this study, we developed six kinds of novel magnetic iron oxide nanoparticles, which are electrically charged by cationic end-group substitution of dextran. Each of the nanoparticles consisted of a small monocrystalline, superparamagnetic iron oxide core that is stabilized by a cross-linked aminated dextran coating to improve stability. We also used three different commercially available nanoparticles for controls. The labeling efficiency of the novel nanoparticles was evaluated, and the feasibility of the imaging by MRI was assessed. The positive-charged nanoparticles were transduced into a -cell line, MIN6 cells, but not three commercially available nanoparticles. MRI showed a marked decrease in signal intensity on T1- and T2-weighted images at the site of the labeled cells in vitro. These data suggest that novel positive-charged nanoparticles could be useful MRI contrast agents to monitor islet mass after transplantation.

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