| Project/Area Number |
02670981
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | University of Tokushima |
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Principal Investigator |
KIWADA Hiroshi Univ.Tokushima,Facul.Pharm.Sci.,Professor, 薬学部, 教授 (50120184)
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| Co-Investigator(Kenkyū-buntansha) |
SUGIYAMA Yuichi Univ.Tokyo,Facul.Pharm.Sci.,Professor, 薬学部, 教授 (80090471)
HARASHIMA Hideyoshi Univ.Tokushima,Facul.Pharm.Sci.,Assoc.Professor, 薬学部, 助教授 (00183567)
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| Project Period (FY) |
1990 – 1992
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| Project Status |
Completed (Fiscal Year 1992)
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| Budget Amount *help |
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1992: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1991: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
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| Keywords | Drug delivery system / Liposome / Macrophage / Lysosome / Opsonin / Complement receptor / Pharmacokinetics / リポソ-ム / 細胞内運命 / DDS / クリアランス / 補体 |
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| Research Abstract |
The usefulness of liposomes as drug carriers has been widely studied in the world, especially on the uptake mechanism by the liver. However,very few studies on the intracellular fate of internalized liposomes have been reported under the common understanding that they are transferred to lysosomes and degradated there. Control of the intracellular fate such as escape of transfer to lysosome and degradation has never been attempted. It is very important to consider the intracellular fate of liposomes after internalization for the development of useful drug delivery system utilizing liposomes as well as the targetability after intravenous injection.
This research was carried out to elucidate the intracellular fate of liposomes and following results were obtained: (1)Perfusion study using rat liver revealed that liposomes were opsonized by plasma protein depending on their particle size. (2)By infusion study,it was found that the saturation process of liver uptake was not expressed by conventional Michaelis-Menten kinetics but by novel kinetic model in which the uptake clearance was decreased by increasing accumulated amount of liposomes in the liver,not by blood concentration. (3)It became apparent that liposomes modified with cetylmannoside were not taken up by kupffer cells via mannose receptor on the cells surface as commonly expected,and the contribution of complement receptors was suggested on the uptake. (4)The method for quantitative estimation of degradation process in lysosomes was presented,and the pharmacokinetic analysis of the data obtained from in vivo and in vitro experiments by this methods made it possible to evaluate the degradation process in the cells quantitatively.
Findings obtained in this study are considered to give very useful informations for development of liposomal drug carriers. As next step of the research,the relationship between internalization process and intracellular fate of liposomes will be focussed.
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