2021/12/22 更新

写真a

アケヒ マサル
明日 卓
AKEHI Masaru
所属
医歯薬学域 助教(特任)
職名
助教(特任)
外部リンク

学位

  • 修士(工学) ( 2011年3月   倉敷芸術科学大学 )

 

論文

  • A Novel Zr-89-labeled DDS Device Utilizing Human IgG Variant (scFv): "Lactosome" Nanoparticle-Based Theranostics for PET Imaging and Targeted Therapy

    Melissa Siaw Han Lim, Takashi Ohtsuki, Fumiaki Takenaka, Kazuko Kobayashi, Masaru Akehi, Hirotaka Uji, Hirotsugu Kobuchi, Takanori Sasaki, Eiichi Ozeki, Eiji Matsuura

    LIFE-BASEL   11 ( 2 )   2021年2月

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    記述言語:英語   出版者・発行元:MDPI  

    "Theranostics," a new concept of medical advances featuring a fusion of therapeutic and diagnostic systems, provides promising prospects in personalized medicine, especially cancer. The theranostics system comprises a novel Zr-89-labeled drug delivery system (DDS), derived from the novel biodegradable polymeric micelle, "Lactosome" nanoparticles conjugated with specific shortened IgG variant, and aims to successfully deliver therapeutically effective molecules, such as the apoptosis-inducing small interfering RNA (siRNA) intracellularly while offering simultaneous tumor visualization via PET imaging. A 27 kDa-human single chain variable fragment (scFv) of IgG to establish clinically applicable PET imaging and theranostics in cancer medicine was fabricated to target mesothelin (MSLN), a 40 kDa-differentiation-related cell surface glycoprotein antigen, which is frequently and highly expressed by malignant tumors. This system coupled with the cell penetrating peptide (CPP)-modified and photosensitizer (e.g., 5, 10, 15, 20-tetrakis (4-aminophenyl) porphyrin (TPP))-loaded Lactosome particles for photochemical internalized (PCI) driven intracellular siRNA delivery and the combination of 5-aminolevulinic acid (ALA) photodynamic therapy (PDT) offers a promising nano-theranostic-based cancer therapy via its targeted apoptosis-inducing feature. This review focuses on the combined advances in nanotechnology and material sciences utilizing the "Zr-89-labeled CPP and TPP-loaded Lactosome particles" and future directions based on important milestones and recent developments in this platform.

    DOI: 10.3390/life11020158

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  • Novel single-chain variant of antibody against mesothelin established by phage library

    Hiromasa Yakushiji, Kazuko Kobayashi, Fumiaki Takenaka, Yoshiro Kishi, Midori Shinohara, Masaru Akehi, Takanori Sasaki, Eiji Ohno, Eiji Matsuura

    CANCER SCIENCE   110 ( 9 )   2722 - 2733   2019年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Mesothelin (MSLN) shows increased expression in various cancer cells. For clinical application of antibodies as a positron emission tomography (PET) imaging reagent, a human shortened antibody is essential both for avoiding redundant immune responses and for providing rapid imaging. Therefore, we cloned a single-chain fragment of variable regions (scFv) from a human-derived gene sequence. This was achieved through the construction of a naive phage library derived from human tonsil lymphocytes. Using a column with human recombinant MSLN, we carried out bio-panning of phage-variants by colony formation. We first obtained 120 clones that were subjected to selection in an ELISA using human recombinant MSLN as a solid phase antigen, and 15 phage clones of scFv with a different sequence were selected and investigated by flow cytometry (FCM). Then, six variants were selected and the individual scFv gene was synthesized in the V-L and V-H domains and expressed in Chinese hamster ovary cells. Mammalian cell-derived human-origin scFv clones were analyzed by FCM again, and one MSLN highly specific scFv clone was established. PET imaging by Zr-89-labeled scFv was done in mice bearing xenografts with MSLN-expressing cancer cells, and tumor legions were successfully visualized. The scFv variant established in the present study may be potentially useful for cancer diagnosis by PET imaging. Mesothelin (MSLN) shows increased expression in various cancer cells. For clinical application of antibodies as a PET imaging reagent, a human shortened antibody is essential both for avoiding redundant immune responses and for providing rapid imaging. Therefore, we cloned a single-chain fragment of variable regions (scFv) from a human-derived gene sequence. This was achieved through the construction of a naive phage library derived from human tonsil lymphocytes.

    DOI: 10.1111/cas.14150

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  • F-containing retinoid X receptor (RXR) partial agonist F-CBt-PMN whose tissue transferability is affected by coadministration of another RXR ligand

    Yuta Takamura, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Masaru Akehi, Takanori Sasaki, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   258   2019年8月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

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  • Fluorine-18 (F-18)-labeled retinoid x receptor (RXR) partial agonist whose tissue transferability is affected by other RXR ligands

    Yuta Takamura, Osamu Shibahara, Masaki Watanabe, Michiko Fujihara, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Hiroyuki Hirano, Hiroki Kakuta

    BIOORGANIC & MEDICINAL CHEMISTRY   27 ( 14 )   3128 - 3134   2019年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Bexarotene (1), a retinoid X receptor (RXR) agonist approved for the treatment of cutaneous T cell lymphoma (CTCL), was reported to migrate into baboon brain based on findings obtained by positron emission tomography (PET) with a C-11-labeled tracer. However, co-administration of non-radioactive 1 had no effect on the distribution of [C-11]1, probably due to non-specific binding of 1 as a result of its high lipophilicity. Here, we report a fluorine-18 (F-18)-labeled PET tracer [F-18] 6 derived from RXR partial agonist CBt-PMN (2), which has lower lipophilicity and weaker RXR-binding ability than [C-11]1. The concomitant administration of 1 or 2 with [F-18]6 with resulted in decreased accumulation of [F-18]6 in liver, together with increased brain uptake and increased accumulation in kidney and muscle, as visualized by PET. A plausible explanation of these findings is the inhibition of [F-18]6 uptake into the liver by concomitantly administered 1 or 2, leading to an increase in blood concentration of [F-18]6 followed by increased accumulation in other tissues.

    DOI: 10.1016/j.bmc.2019.05.045

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  • Synthesis of C-11-Labeled RXR Partial Agonist 1-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [C-11]Carbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof (vol 60, pg 7139 , 2017)

    Osamu Shibahara, Masaki Watanabe, Yuta Takamura, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Hiroyuki Hirano, Shunsuke Nakatani, Hiromi Nishioka, Yasuo Takeuchi, Hiroki Kakuta

    JOURNAL OF MEDICINAL CHEMISTRY   62 ( 9 )   4780 - 4781   2019年5月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

    DOI: 10.1021/acs.jmedchem.9b00617

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  • Novel human anti-mesothelin scFv for cancer targeted therapy

    Hiromasa Yakushiji, Kazuko Kobayashi, Fumiaki Takenaka, Masaru Akehi, Eiji Ohno, Eiji Matsuura

    CANCER SCIENCE   109   549 - 549   2018年12月

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    記述言語:英語   出版者・発行元:WILEY  

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  • Anti-high Mobility Group Box 1 Antibody Ameliorates Albuminuria in MRL/lpr Lupus-Prone Mice

    Haruki Watanabe, Katsue S. Watanabe, Keyue Liu, Sumie Hiramatsu, Sonia Zeggar, Eri Katsuyama, Noriko Tatebe, Akiya Akahoshi, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Takanori Sasaki, Ken-ei Sada, Eiji Matsuura, Masahiro Nishibori, Jun Wada

    MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT   6   31 - 39   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:CELL PRESS  

    We evaluated the efficacy of a neutralizing anti-high mobility group box 1 (HMGB1) monoclonal antibody in MRL/lpr lupus-prone mice. The anti-HMGB1 monoclonal antibody (5 mg/kg weight) or class-matched control immunoglobulin G2a (IgG2a) was administered intravenously twice a week for 4-15 weeks. Urine albumin was monitored, and histological evaluation of the kidneys was conducted at 16 weeks. Lymphadenopathies were evaluated by 1-(2'-deoxy-2'-[F-18]fluoro-beta-D-arabinofuranosyl) cytosine ([F-18] FAC) positron emission tomography/computed tomography (PET/CT) at 12 weeks. Following 4-week treatment, [F-18]FAC-PET/CT showed similar accumulation in cervical and axillary lymph nodes at 12 weeks of age. However, anti-HMGB1 monoclonal antibody sufficiently inhibited the increase in albuminuria compared to an isotype control following 15-week treatment. Complement deposition was also improved; however, there were no significant differences in IgG deposition and renal pathological scores between the two groups. Anti-double-stranded DNA (dsDNA) antibody titers and cytokine and chemokine levels were also unaltered. Although there were no significant differences in glomerular macrophage infiltration, neutrophil infiltration was significantly decreased by the anti-HMGB1 monoclonal antibody. Antagonizing HMGB1 treatment suppressed HMGB1 translocation from nuclei in the kidney and suppressed neutrophil extracellular traps. The anti-HMGB1 monoclonal antibody demonstrated therapeutic potential against albuminuria in lupus nephritis by inhibiting neutrophil recruitment and neutrophil extracellular traps.

    DOI: 10.1016/j.omtm.2017.05.006

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  • Synthesis of C-11-Labeled RXR Partial Agonist 14(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)aminoThenzotriazole-5-carboxylic Acid (CBt-PMN) by Direct [C-11]Carbon Dioxide Fixation via Organolithiation of Trialkyltin Precursor and PET Imaging Thereof

    Osamu Shibahara, Masaki Watanabe, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Hiroyuki Hirano, Shunsuke Nakatani, Hiromi Nishioka, Yasuo Takeuchi, Hiroki Kakuta

    JOURNAL OF MEDICINAL CHEMISTRY   60 ( 16 )   7139 - 7145   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    The retinoid X receptor (RXR) partial agonist 1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic acid (1; CBt-PMN, E-max = 75%, EC50 = 143 nM) is a candidate for treatment of central nervous system (CNS) diseases such as Alzheimers and Parkinsons diseases based on reports that RXR-full agonist 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) shows therapeutic effects on these disease in rodent models. Here, we synthesized carbon-11-labeled ([C-11]1) as a tracer for positron emission tomography (PET) and used it in a PET imaging study to examine the brain uptake and biodistribution of 1. We found that (CO2)-C-11 fixation after tinlithium exchange at -20 degrees C afforded [C-11]1. This methodology may also be useful for synthesizing (CO2H)-C-11-PET tracer derivatives of other compounds bearing pi-rich heterocyclic rings. A PET/CT imaging study of [C-11]1 in mice indicated 1 is distributed to the brain and is thus a candidate for treatment of CNS diseases.

    DOI: 10.1021/acs.jmedchem.7b00817

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  • Synthesis of 11C labeled RXR partial agonist CBt-PMN by [11C] carbon dioxide fixation via organolithiation of trialkyltin precursor and PET imaging thereof

    Osamu Shibahara, Masaki Watanabe, Masaru Akehi, Takanori Sasaki, Takahisa Hanada, Akiya Akahoshi, Hiroyuki Hirano, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   254   2017年8月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

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  • Evaluation of brain migration and therapeutic effects of novel RXR partial agonist CBt-PMN on cognitive impairment in mice

    Toshiki Kobayashi, Osamu Shibahara, Masaki Watanabe, Shoya Yamada, Masaru Akehi, Takanori Sasaki, Takahisa Hanada, Akiya Akahoshi, Hiroyuki Hirano, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   252   2016年8月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

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  • The Function of beta 2-glycoprotein I in Angiogenesis and Its in Vivo Distribution in Tumor Xenografts

    Arum Tri Wahyuningsih, Lianhua Shen, Kazuko Kobayashi, Takanori Sasaki, Fumiaki Takenaka, Takahisa Hanada, Masaru Akehi, Akiya Akahoshi, Eiichi Ozeki, Eiji Ando, Eiji Matsuura

    ACTA MEDICA OKAYAMA   70 ( 1 )   13 - 24   2016年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Intact beta 2-glycoprotein I (i beta 2GPI) is a glycoprotein that regulates coagulation and fibrinolysis. Nicked beta 2GPI (n beta 2GPI) possesses an angiogenic property at a relatively low concentration, and an anti-angiogenic property at a high concentration. Here we investigated the functions of i beta 2GPI and n beta 2GPI in vascular endothelial growth factor (VEGF)-A-induced endothelial cell proliferation and tube formation. We used noninvasive PET imaging to analyze the in vivo distribution of intravenously injected beta 2GPI variants in tumor lesions in mice. i beta 2GPI was incubated with plasmin to obtain n beta 2GPI, and its N-terminal sequence was analyzed. n beta 2GPI had at least one other cleavage site upstream of the beta 2GPFs domain V, whereas the former plasmin-cleavage site locates between K-317 and T-318. Both of intact and nicked beta 2GPI significantly inhibited the VEGF-A-induced cell proliferation and the tube formation of human umbilical vein endothelial cells (HUVECs). PET imaging visualized considerably distributed intensities of all tested beta 2GPI variants in tumor lesions of pancreatic tumor cell-xenografts. These results indicate that beta 2GPI may be physiologically and pathophysiologically important in the regulation of not only coagulation and fibrinolysis, but also angiogenesis.

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  • Chiral 1-(1,3-dithian-2-yl) prop-2-en-1-ols: new scaffolds for enantiopure alpha-hydroxyaldehydes

    Masaru Akehi, Mariko Kawamoto, Tadakatsu Mandai

    TETRAHEDRON   71 ( 37 )   6488 - 6498   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    We have demonstrated that chiral 1-(1,3-dithian-2-yl)prop-2-en-1-ols as new scaffolds, obtained by enzyme-catalyzed kinetic resolution, undergo Suzuki-Miyaura cross-couplings and hydroformylation smoothly. Also, we have found that a 1,3-dithianyl group of the products can be removed without any erosion of the enantiopurity under mild conditions. A new access to a variety of enantiopure alpha-hydroxyaldehydes with ensured absolute configuration is described. (C) 2015 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2015.05.039

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  • Positron Emission Tomography to Elucidate Pharmacokinetic Differences of Regioisomeric Retinoid X Receptor Agonists

    Toshiki Kobayashi, Yuki Furusawa, Shoya Yamada, Masaru Akehi, Fumiaki Takenaka, Takanori Sasaki, Akiya Akahoshi, Takahisa Hanada, Eiji Matsuura, Hiroyuki Hirano, Akihiro Tai, Hiroki Kakuta

    ACS MEDICINAL CHEMISTRY LETTERS   6 ( 3 )   334 - 338   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    RXR partial agonist NEt-41B (2a, 6-[ethyl-(4-isobutoxy-3-isopropylphenyl)amino]pyridine-3-carboxylic acid: EC50 = 169 nM, E-max = 55%) showed a blood concentration higher than its Emax after single oral administration at 30 mg/kg to mice, and repeated oral administration at 10 mg/kg/day to KK-A(y) mice afforded antitype 2 diabetes activity without the side effects caused by RXR full agonists. However, RXR full agonist NEt-3IB (la), in which the isobutoxy and isopropyl groups of 2a are interchanged, gave a much lower blood concentration than 2a. Here we used positron emission tomography (PET) with tracers [C-11] la, [C-11]2a and fluorinated derivatives [F-18] lb, [F-18]2b, which have longer half-lives, to examine the reason why la and 2a exhibited significantly different blood concentrations. As a result, the reason for the high blood concentration of 2a after oral administration was found to be linked to higher intestinal absorbability together with lower biliary excretion, compared with la.

    DOI: 10.1021/ml500511m

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  • Elucidation of the pharmacokinetic difference of regioisomeric retinoid X receptor agonists having an alkoxy group by PET imaging

    Toshiki Kobayashi, Kohei Kawata, Mariko Nakayama, Yuki Furusawa, Shoya Yamada, Hiroyuki Hirano, Fumiaki Takenaka, Masaru Akehi, Takanori Sasaki, Eiji Matsuura, Akihiro Tai, Hiroki Kakuta

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248   2014年8月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

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  • KINETIC RESOLUTION OF SECONDARY ALCOHOLS BY CHIRAL DMAP DERIVATIVES PREPARED BY THE UGI MULTICOMPONENT REACTION

    Hiroki Mandai, Shunsuke Irie, Masaru Akehi, Kazunobu Yuri, Masaaki Yoden, Koichi Mitsudo, Seiji Suga

    HETEROCYCLES   87 ( 2 )   329 - 340   2013年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The kinetic resolution of secondary alcohols was examined by new chiral DMAP derivatives, which can readily be prepared by the Ugi multicomponent reaction in a one-pot operation. The initial screening of DMAP derivatives indicated that the catalyst bearing L-valine with an S configuration at the a-position of amide showed the best stereoselectivity factor. After the reaction conditions were optimized with (S,S)-4a in the kinetic resolution of secondary alcohols, various acyclic and cyclic secondary alcohols could be resolved with an s-factor of up to 12.

    DOI: 10.3987/COM-12-12624

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