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Optimization of drug delivery system for antitumor agents based on the energy metabolism inhibition of tumor cells

Research Project

Project/Area Number 09557197
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Biological pharmacy
Research InstitutionThe University of Tokushima, Faculty of Pharmaceutical Sciences

Principal Investigator

HARASHIMA Hideyoshi  The University of Tokushima, aculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (00183567)

Co-Investigator(Kenkyū-buntansha) TERASAKI Tetsuya  Tohoku University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (60155463)
SHINOHARA Yasuo  The University of Tokushima, Faculty of Pharmaceutical Sciences, Associate Profe, 薬学部, 助教授 (60226157)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 1998: ¥5,300,000 (Direct Cost: ¥5,300,000)
Fiscal Year 1997: ¥7,000,000 (Direct Cost: ¥7,000,000)
KeywordsDrug delivery system / Liposomes / Tumor / Gene / エネルギー代謝 / 抗がん剤 / アンチセンス
Research Abstract

The objective of this study is to develop an optimum drug delivery system to increase antitumor effect by enhancing targeting efficiency of antitumor agents. An artificial carrier system for macromolecules to the nuclei was developed by using a pH-sensitive liposomes, which can enhance cytosolic escape of liposomally encapsulated macromolecules depending on the intra-endosomal pH decrease. The cytosolic delivery of macromolecules was confirmed by confocal laser microscopy. In addition, nuclear targeting of macromoleules was achieved by adding a nuclear localization signal (NLS) to the molecules. The FITC-labelled albumin, which can not be passively delivered to nucleus, was successfully targeted to nucleus by adding NLS.This system for intracellular control of macromolecules can be a basic strategy to manipulate intracellular trafficking of high molecular weight compounds. On the other hand, it has been shown that hexokinase type-II is specifically transcripted in tumor cells and this can be a target enzyme to be inhibited. We aimed to deliver DNA to inhibit the transcription of hexokinase-II in tumor cells. To achieve this, the quantitative assay system was required to measure DNA in intracellular organella such as nucleus. We have succeeded to develop a sound assay system to measure intra-nuclear DNA by applying PCR-method. This method provided us an interesting relationship between targeted nuclear DNA and transcription activity. By using this newly developed intracellular regulation system and quantitative assay method, we will be able to optimize rational drug carrier system to inhibit transcription in tumor cells.

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] 浦上裕美子他: "リポソームによる抗癌剤の抗腫瘍効果の最適化に関する速度論的研究:生理学的モデルに基づいたシミュレーションスタディー" Drug Delivery System. 12. 403-408 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] R.Tachibana et al.: "Intracellular regulation of macromolecules using pH-sensitive liposomes and nuclear localization signal:Quantitative and aualitative evaluation" Biochem.Biophys.Res.Comm.251. 538-544 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 原島秀吉他: "キャリアーによる細胞内デリバリー戦略と今後の課題" Drug Delivery System. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Shinohara et al.: "Source of ATP for hexokinase-catalized glucose phosphorylation in tumor cells" Biochim.Biophys.Acta. 1319. 319-330 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Shinohara et al.: "Quantitative determinations of the steady state transcript levels of hexokinase isozymes and glucoce transporter isomers in normal rat" Biochim.Biophys.Acta. 1368. 129-136 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Kitazawa et al.: "Efflux of taurocholic acid across the blood-brain barrier:Interaction with cyclic peptides" J.Pharm.Exp.Ther.286. 890-895 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] R.Tachibana, H.Harashima, M.Shono, M.Azumano, M.Niwa, S.Futaki and H.Kiwada: "Intracellular Regulation of Macromolecules Using pH-Sensitive Liposomes and Nuclear Localization Signal : Qualitative and Quantitative Evaluation of Intracellular Trafficking" Biochem.Biophys.Res.Comm.251. 538-544 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] M.Kuwajima, H.Harashima, M.Hayashi, S.Ise, M.Sei, K.Lu, H.Kiwada, Y.Sugiyama, K.Shima: "Pharmacokinetic analysis on the cardioprotective effect of 3- (2, 2, 2-trimethyl hydrazinium) propionate in mice : Inhibition of carnitine transporter in kidney." J.Pharm.Exp.Ther.(in press).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Shinohara, I.Sagawa, J.Ichihara, K.Yamamoto, K.Terao and H.Terada: "Source of ATP for hexokinase-catalyzed glucose phosphorylation in tumor cells : Dependence on the rate of oxidative phosphorylation to that of extramitochondrial ATP generation" Biochim.Biophys.Acta. 1319. 319-330 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Daikoku, Y.Shinohara, A.Shima, N.Yamazaki and H.Terada: "Dramatic enhancement of the specific expression of the heart-type fatty acid binding protein in rat brown adipose tissue by cold exposure" FEBS Lett.410. 383-386 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Y.Shinohara, K.Yamamoto, K.Inoo, N.Yamazaki and H.Terada: "Quantitative determinations of the steady state transcript levels of hexokinase isozymes and glucose transporter isoforms in normal rat tissues and the malignant tumor cell line AH130" Biochim.Biophys.Acta. 1368. 129-136 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] T.Kitazawa, T.Terasaki, H.Suzuki, A.Kakee and Y.Sugiyama: "Efflux of taurocholic acid across the blood-brain barrier : Interaction with cyclic peptides." J.Pharm.Exp.Ther.286. 890-895 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] 浦上裕美子他: "リポソームによる抗癌剤の抗腫瘍効果の最適化に関する速度論的研究:生理学的モデルに基づいたシミュレーションスタディー" Drug Delivery System. 12. 403-408 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] R.Tachibana et al.: "Intracellular regulation of macromolecules using pH-sensitive liposomes and nuclear localization signal:Quantitative and qualitative evaluation" Biochem.Biophys.Res.Comm.251. 538-544 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 原島秀吉他: "キャリアーによる細胞内デリバリー戦略と今後の課題" Drug Delivery System. (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Shinohara et al.: "Source of ATP for hexokinase-catalized glucose phosphorylation in tumor cells" Biochim.Biophys.Acta. 1319. 319-330 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Y.Shinohara et al.: "Quantitative determinations of the steady stato transcript levels of hexokinase isozymes and glucose transporter isomers in normal rat" Biochim.Biophys.Acta. 1368. 129-136 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] T.Kitazawa et al.: "Efflux of taurocholic acid across the blood-brain barrier:Interaction with cyclic peptides" J.Pharm.Exp.Ther.286. 890-895 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 浦上裕美子 他: "リポソームによる抗癌剤の抗腫瘍効果の最適化に関する速度論的研究:生理学的モデルに基づいたシミュレーションスタディー" Drug Delivery System. 12. 403-408 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] 島田貫浩 他: "In vivo競合実験によるリポソームの肝取込クリアランスの飽和性を記述する満腹モデルの検証" 薬剤学. 57. 197-203 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Shinohara, et al.: "Source of ATP for hexokinace-catalized glucose phosphorylation in tumor ceus." Biochim.Biophys.Acta. 1319. 319-330 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Y.Shinohara, et al.: "Quantitative determinations of the steady state transcript levels of hexokinace isozymes and glucoce transporter isotorms in nomal" Bichim.Biophys.Acta. 1368. 129-136 (1998)

    • Related Report
      1997 Annual Research Report
  • [Publications] J.Komura, et al.: "Brain-to-blood active transport of β-alaniro across the blood-brain barrier." FEBS Let.400. 131-135 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] W.Wang, et al.: "Efficlent delivery of clrculating Poliovirus to the central nervous system in depondently of Poliovirus Receptor." Virology. 229. 421-428 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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