• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to project page

2010 Fiscal Year Annual Research Report

抗ラジカル型抗炎症剤XO阻害剤AHPPの新しいSMA-ミセル化剤の研究

Research Project

Project/Area Number 20590049
Research InstitutionSojo University

Principal Investigator

前田 浩  崇城大学, 薬学部, 教授 (90004613)

Co-Investigator(Kenkyū-buntansha) 方 軍  崇城大学, 薬学部, 准教授 (20412736)
中村 秀明  崇城大学, 薬学部, 助手 (30435151)
KeywordsXO阻害剤 / 徐放性 / DDS / 降圧剤 / 水可溶化 / NOの寿命延長 / ナノメディシン / PEG化医薬
Research Abstract

我々は体内で生ずるスーパーオキサイドアニオンラジカル(O_2^-)が感染、炎症、さらには虚血再環流時などでの生体組織傷害の重要な要因であり、そのO_2^-の多くはその産生酵素のキサンチンオキシダーゼ(XO)の誘導とその活性に起因することを明らかにしている。そこで、このXOの阻害剤を用いて医薬にする可能性を追及した。既にAHPP(4-アミノ-6-ヒドロキシピラゾロ-3,4-ピリミジン[AHPP])がXOの強力な阻害剤を見出しているが、この医薬品化における困難性はAHPPの水難溶性であることと、低分子であるために体外排泄が急速で、作用時間が短すぎ、これまた実用化のバリヤーであった。
これらの目的を解決するため、AHPPのPEG(ポリエチレングリコール)共有結合体(PEG-AHPP)あるいはスチレンマレイン酸コポリマー(SMA)を用いたSMAの非共有結合抱合ミセル体(SMA-AHPP)を作成した。その結果として(1)In vitroでのXO阻害活性はfreeのAHPPに比べ、PEG-AHPPおよびSMA-AHPPは80%程度あり、満足すべきものであった。(2)In vivoのXO阻害活性はラット肝の虚血再環流(I/R)モデルを用いて行ったところ、薬物非投与群に比べ、充分な細胞傷害作用の抑制をみた。(3)また、本態性高血圧ラット(SHR)を用いた試験では静脈内および経口投与の何れにおいても、平均正常血圧への降下作用を示した。(4)経口投与の場合でも、1回の投与でもその作用は24時間以上持続した。
今後は、とくにeNOSによるNO放出はAHPPによるXOの阻害によりO_2^-の産生が抑制され、NOの血管拡張作用が向上するので、AHPP-ArgのようなNO産生成分を含有する高分Fミセル化化合物を用いれば、よりAHPPの作用を増幅することが考えられる。

  • Research Products

    (17 results)

All 2011 2010

All Journal Article (7 results) (of which Peer Reviewed: 7 results) Presentation (7 results) Book (3 results)

  • [Journal Article] History and impact of EPR effect for the nanomedicine drug developments in cancer chemotherapy2011

    • Author(s)
      H.Maeda, Y.Matsumura
    • Journal Title

      Advanced Drug Delivery Reviews

      Volume: (available online)

    • Peer Reviewed
  • [Journal Article] EPR effect : the unique characteristics of tumor blood vessels for drug delivery, factors involved, its limitation and augmentation2011

    • Author(s)
      J.Fang, H.Nakamura, H.Maeda
    • Journal Title

      Advanced Drug Delivery Reviews

      Volume: (available online)

    • Peer Reviewed
  • [Journal Article] Intracellular uptake and behavior of two types zinc protoporphyrin (ZnPP) micelles, SMA-ZnPP and PEG-ZnPP as anticancer agents ; Unique intracellular disintegration of SMA micelles2011

    • Author(s)
      H.Nakamura, J.Fang, B.Gahininath, K.Tsukigawa, H.Maeda
    • Journal Title

      J.Controlled Release

      Volume: (accepted)

    • Peer Reviewed
  • [Journal Article] Synthesis and evaluation of poly(styrene-co-maleic acid) micellar nanocarriers for the delivery of tanespimycin2011

    • Author(s)
      N.Larson, K.Greish, H.Bauer, H.Maeda, H.Ghandehari
    • Journal Title

      International Journal of Pharmaceutics

      Volume: (in preparation)

    • Peer Reviewed
  • [Journal Article] Nitroglycerin enhances vascular blood flow and drug delivery in hypoxic tumor tissues : Analogy between angina pectoris and solid tumors and enhancement of the EPR effect2010

    • Author(s)
      Hiroshi Maeda
    • Journal Title

      J.Control Release

      Volume: 142 Pages: 296-298

    • Peer Reviewed
  • [Journal Article] Tumor-selective delivery of macromolecular drugs via the EPR effect : Background and future prospects2010

    • Author(s)
      Hiroshi Maeda
    • Journal Title

      Bioconjugate Chemistry

      Volume: 21 Pages: 797-802

    • Peer Reviewed
  • [Journal Article] Tissue protective effect of xanthine oxidase inhibitor, polymer conjugate SMA-AHPP, on hepatic ischemia-reperfusion injury2010

    • Author(s)
      J.Fang, T.Seki, H.Qin, G.Y.Bharate, A.K.Iyer, H.Maeda
    • Journal Title

      Experimental Biology and Medicine

      Volume: 235 Pages: 487-496

    • Peer Reviewed
  • [Presentation] Nanoparticles of styrene-co-maleic acid (SMA) telomer containing anthracyclin and zinc-protoporphyrin (ZnPP) as new miceller anticancer agents, and SMA conjugate of AHPP, a xanthine oxidase inhibitor for oxystress diseases2011

    • Author(s)
      H.Maeda, H.Nakamura, G.Y.Bharate, K.Tsukigawa, H.Qin, J.Fang
    • Organizer
      International Conference on Biomaterials Science 2011
    • Place of Presentation
      つくば市(茨城県)(Review)
    • Year and Date
      2011-03-17
  • [Presentation] Evaluation of (styrene-co-maleic acid) telomer micelles encapsulated-zinc protoporphyrin (SMA-ZnPP) : A stability study for three different types of SMA micelles2011

    • Author(s)
      G.Y.Bharate, H.Nakamura, J.Fang, B.Klumperman, S.Shinkai, H.Maeda
    • Organizer
      International Conference on Biomaterials Science 2011
    • Place of Presentation
      つくば市(茨城県)
    • Year and Date
      2011-03-17
  • [Presentation] The enhanced permeability and retention effect in cancer and inflammation for more selective drug delivery : Past, present and future outlook2010

    • Author(s)
      Hiroshi Maeda
    • Organizer
      37th Annual Meeting and Exposition of the Controlled Release Society
    • Place of Presentation
      オレゴン州ポートランド(米国)
    • Year and Date
      2010-07-13
  • [Presentation] ニトロ剤による腫瘍デリバリーの増強とその臨床成績、基礎2010

    • Author(s)
      前田浩、方軍、中村秀明、J.Daruwalla
    • Organizer
      第26回日本DDS学会
    • Place of Presentation
      大阪
    • Year and Date
      2010-06-18
  • [Presentation] Nitroglycerin facilitates tumor drug delivery via augmentation of vascular permeability involving NO generation in the hypoxic tumor tissue2010

    • Author(s)
      H.Maeda, H.Nakamura, J.Fang
    • Organizer
      The 6th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide
    • Place of Presentation
      京都
    • Year and Date
      2010-06-17
  • [Presentation] Limitations and augmentations of the EPR effect in solid tumor2010

    • Author(s)
      H.Maeda, H.Nakamura, J.Fang
    • Organizer
      8^<th> Int'l Symposium Polymer Therapeutic
    • Place of Presentation
      バレンシア(スペイン)
    • Year and Date
      2010-05-26
  • [Presentation] The EPR effect for tumor selective drug targeting : Its mechanism and future outlook2010

    • Author(s)
      Hiroshi Maeda
    • Organizer
      International Advanced Drug Delivery Symposium
    • Place of Presentation
      台湾
    • Year and Date
      2010-04-30
  • [Book] Recollections of 45 years in research : From protein chemistry to polymeric drugs to the EPR effect in cancer therapy In Rapidly Changing World2011

    • Author(s)
      Hiroshi Maeda
    • Publisher
      Nova Science Publishers, Inc.(in press)
  • [Book] Liver tumor targeting In Drug Delivery in Oncology. From Basic Research to Cancer Therapy2011

    • Author(s)
      K.Hochdorffer, G.DiStefano, L.Fiume, H.Maeda, F.Kratz
    • Publisher
      Wiley-VCH Verlag GmbH & Co.KG, Weinhein, Germany(in press)
  • [Book] The EPR-effect in Relation to Tumor Targeting In Drug Delivery in Oncology. From Basic Research to Cancer Therapy2010

    • Author(s)
      H.Maeda
    • Publisher
      Wiley-VCH Verlag GmbH & Co.KG, Weinhein, Germany(in press)

URL: 

Published: 2012-07-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi