1995 Fiscal Year Final Research Report Summary
Uptake mechanism and intracellular destiny of liposomes in RES
| Project/Area Number |
05671783
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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 | The University of Tokushima, Faculty of Pharmaceutical Sciences |
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Principal Investigator |
HARASHIMA Hideyoshi The University of Tokushima, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (00183567)
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| Co-Investigator(Kenkyū-buntansha) |
KIWADA Hiroshi The University of Tokushima, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50120184)
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| Project Period (FY) |
1993 – 1995
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| Keywords | Drug delivery system / Pharmacokinetics / Liposomes / Opsonin / Complement receptor / Saturation / Diameter |
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| 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".
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