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Uptake mechanism and intracellular destiny of liposomes in RES

Research Project

Project/Area Number 05671783
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Physical pharmacy
Research InstitutionThe University of Tokushima, Faculty of Pharmaceutical Sciences

Principal Investigator

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

Co-Investigator(Kenkyū-buntansha) KIWADA Hiroshi  The University of Tokushima, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50120184)
Project Period (FY) 1993 – 1995
Project Status Completed (Fiscal Year 1995)
Budget Amount *help
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1993: ¥700,000 (Direct Cost: ¥700,000)
KeywordsDrug delivery system / Pharmacokinetics / Liposomes / Opsonin / Complement receptor / Saturation / Diameter
Research Abstract

The objective of this study is to clarify the relationship between uptake mechanism of liposomes by the reticuloendothelial system (RES) and the intracellular destiny of liposomes. The saturation manner of liposome uptake by the liver was examined kinetically in rats. The saturation characteristics of liposomes by the liver was explained well with the area under the curve of blood concentration and not by the blood concentration itself. New model was postulated for this saturation kinetics as "satiated model". The kinetic analysis revealed that there were at least two kinds of uptake pathways in liver, one is the high clearance/low capacity and low clearance/high capacity pathway. The uptake mechanism of liposomes by the liver was then examined under the isolated perfused liver system, and the contribution of complement receptor mediated phagocytosis was shown. The activation of complement system was dependent on the size of liposomes and the enhanced uptake by the liver resulted from the size dependent opsonization of liposomes. This complement receptor mediated uptake pathway corresponded to the high clearance/low capacity pathway. The effect of liposome dose on the intracellular degradation of liposomes in RES was also investigated. There were at least two kinds of degradation processes in the liver. This heterogeneity in the degradation of liposomes can be explained by both "Sorting Model" which assumes the heterogenous degradation processes and "Traffic Jam Model" which assumes the heterogenous transport processes. The intracellular transport of liposomes into acidic compartment was analyzed under peritoneal macrophages using pH-sensitive dye and it was clarified that the dose of liposomes influenced the transport processes of liposomes before fusion with lysosomes, which supported the "Traffic Jam Model".

Report

(4 results)
  • 1995 Annual Research Report   Final Research Report Summary
  • 1994 Annual Research Report
  • 1993 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Hideyoshi Harashima et al.: "Kinetic analysis of AUC-dependent saturable clearance of liposomes : Mathematical description of AUC-dependency" J.Pharmacokinetics and Biopharmaceutics. 21. 299-308 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima et al.: "Enhanced hepatic uptake of liposomes through size dependent complement activation" Pharmaceutical Research. 11. 402-406 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima et al.: "Kinetic modeling of liposome degradation in peritoneal macrophages" Biopharmaceutics and Drug Disposition. 16. 113-123 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] 原島秀吉: "薬物速度論に基づいたリポソームによる薬物送達システムの構築" 薬物動態. 10. 566-575 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Yumi Morioka et al.: "Effect of liposome dose on the intracellular degradation of liposomes." Drug Delivery System. 45. 27-35 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima et al.: "Studies on the hepatic uptake of liposomes with isolated perfused liver system" J.of Liposome Research. (印刷中). (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Yoshihiro Kume, Chizu Yamane and Hiroshi Kiwada.: "Kinetic modeling of liposome degradation in blood circulation." Biopharm.Drug Disp.14. 265-270 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Kazuya Sakata, and Hiroshi Kiwada.: "Distinction between the depletion of opsonins and saturation of uptake in the dose dependent hepatic uptake of liposomes." Pharm.Res.10. 606-610 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Chizu Yamane, Yoshihiro Kume and Hiroshi Kiwada.: "Kinetic analysis of AUC-dependent saturable clearance of liposomes : Mathematical description of AUC-dependency." J.Pharmacokin.Biopharm.21. 299-308 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Kazuuya Sakata, Koichi Funato and Hiroshi Kiwada.: "Enhanced hepatic uptake of liposomes through size dependent complement activation." Pharm.Res.11. 402-406 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Yoshihito Ochi and Hiroshi Kiwada.: "Kinetic modeling of liposome degradation in serum : Effect of size and concentration of liposomes in vitro." Biopharm.Drug Disposit.15. 217-225 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hirotami Matsuo, Koichi Funato, Hideyoshi Harashima and Hiroshi Kieada.: "The complement-but not mannose receptor mediated phagocytosis is involved in the hepatic uptake of cetyl mannoside-medified liposomes." J.Drug Targeting. 2. 141-146 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Noriko Hirai and Hiroshi Kiwada.: "Kinetic modeling of liposome degradation in peritoneal macrophages." Biopharm.Drug Disposit.16. 113-123 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima, Tomoyo Hiraiwa, Yoshihito Ochi, and Hiroshi Kiwada.: "Size dependent liposome degradation in blood : In vivo/in vitro correlation by kinetic modeling." J.Drug Targeting. 3. 253-261 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Yumi Morioka, Hideyoshi Harashima, Koji Yoshimura and Hiroshi Kiwada.: "Effect of liposome dose on the intracellular degradation of liposomes." Drug Delivery Sys. 45. 27-35 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1995 Final Research Report Summary
  • [Publications] Hideyoshi Harashima et al.: "Kinetic modeling of liposome degradation in peritoneal macrophages." Biopharmaceutics and Drug Disposition. 16. 113-123 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Size dependent liposome degradation in blood : In vivo/in vitro correlation by Kinetic modeling." J. of Drug Targeting. 3. 253-261 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 原島秀吉: "薬物速度論に基づいたリポソームによる薬物送達システムの構築" 薬物動態. 10. 566-575 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yumi Morioka et al.: "Effect of liposome dose on the intracellular degradation of liposomes." Drug Delivery System. 45. 27-35 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Studies on the hepatic uptake mechanism of liposomes with isolated perfused liver system." J. Liposome Research. (印刷中). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Liposomal targeting and drug delivery : Kinetic consideration" Advanced Drug Delivery Reviews. (印刷中). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Enhanced hepatic uptake of liposomes through complement activation depending on the size of liposomes" Pharmaceutical Research. 11. 402-406 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hirotami Matsuo et al.: "The complemeut-but not mannose receptor-mediated phagocytosis is involved in hepatic uptake of cetylmannosidl-modified liposomes in ctu" Journal of Drug Targeting. 2. 141-146 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Kinetic modeling of liposome degradation in serum:Effect of size and concentration of lipesomes in vitro" Biopharmaceutics & Drug Disposition. 15. 217-225 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Kinetic modeling of liposome degradation in peritoneal macrophages." Biopharmacentics & Drug Disposition. 15. 872-883 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 原島 秀吉: "リポソームによる薬物送達システムの構築-体内動態から細胞内動態の制御へ向けて" ファルマシア. 30. 496-501 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 原島秀吉 他: "リポソームによるDDSの設計" BIOmedica. 8. 38-43 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Kinetic analysis of AUC-dependent saturable clearance of liposomes:Mathematical description of AUC dependency." J.Pharmacokin.Biopharm.21. 299-308 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Distinction between the depletion of opsonins and the saturation of uptake in the dose dependent hepatic uptake of liposomes." Pharm.Res.10. 606-610 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hideyoshi Harashima et al.: "Enhanced hepatic uptake of liposomes through complement activation depending on the size of liposomes." Pharm.Res.11. 402-406 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Hirotami Matsuo et al.: "The complement-but not mannose receptor-mediated phagocytosis is involved in the hepatic uptake of cetylmannoside modified liposome in situ." J.Drug Targeting. (印刷中). (1994)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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