リポソームの細胞内分解過程に及ぼす投与量の影響

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The purpose of this study is to evaluate quantitatively the intracellular fate of liposomes especially their degradation process in vivo. Multilamellar liposomes were double labeled with 3H-cholesteryl hexadecyl ether (3H-CHE) and with 125I-bovin serum albumin (125I-BSA) and the degradation of liposomes was expressed by the ratio of intact 125I-BSA to 3H-CHE in rat liver. The effect of liposome dose on their degradation in liver was examined after intravenous administration of liposomes at 2, 60, and 200 μmol lipid/kg. The time course of liposome degradation at low dose decreased bi-phasic, indicating at least two degradation processes. A remarkable dose dependency was also observed in the hepatic degradation of liposomes as well as in the hepatic uptake of liposomes. Two kinds of kinetic models were developed to explain these phenomena, one is “Sorting model”, having heterogenous degradation processes, the other is “Traffic-Jam model”, having heterogenous intracellular transport pathways with single degradation process (k1). The dose-dependent liposome degradation in liver was analyzed by these two models. In a Sorting model, the effect of dose was explained by a sorting ratio, f, by which liposomes were sorted into fast and slow degradation compartments. In the Traffic-Jam model, the heterogenous intracellular transport of liposomes was explained by adding a Traffic-Jam compartment to degradation compartment. The effect of dose was reflected on the fraction of liposomes into Traffic-Jam compartment and the volume of Trafic-Jam compartment indicated by kdj/(k1+Kdj) and kdj/kjd, respectively. Since both models could fit the observed data well, model discrimination was not possible based on these study. Further studies to clarify the specific mechanism of these heterogenous intracellular traffic and/or degradation processes are required for the rational strategy in the drug delivery system using liposomes as drug carriers.
日本DDS学会の論文
1996-01-10

リポソームの細胞内分解過程に及ぼす投与量の影響

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