Hepatic Uptake and Tissue Distribution of Liposomes: Influence of Vesicle Size

Abstract

The size-dependent disposition of liposomes in rats was studied. Liposomes consisting of phosphatidylcholine, cholesterol, dicetylphospate and alphatocopherol in a molar ratio of 4:4:1:1, containing a trace of [¹⁴C]-labeled cholesterol as a marker of the lipid phase, were prepared and sized by extruding through polycarbonate membrane. [³H]-inulin was used as a marker of the aqueous phase. In situ liver perfusion in rats showed that hepatic extraction of liposomes was significant for multilamellar vesicles (MLVs) larger than 0.4 μm (0.40, 0.82 and 1.31 μm) and small unilamellar vesicles (SUV), but negligible for 0.25 μm MLV. Pharmacokinetic analysis after intravenous (i.v.) injection showed that the area under the plasma elimination curve (AUC) was significantly higher, but the volume of distribution (Vd) and the elimination rate constant (ke) were significantly lower for the 0.25 μm than for the 1.31 μm liposomes. Comparing the distribution of 1.36 and 0.25 μm MLVs after i.v. injection, the 1.31 μm MLV showed a significantly higher concentration in liver and spleen, but lower concentration in plasma and kidney, than the 0.26 μm in terms of dose percent. These results suggest that size is one of the important factors affecting the fate of liposmes in vivo. There must be a minimun size for effective uptake of liposomes by the reticuloendothelial system. If below the minimum effective uptake size, the MLV should remain in higher concentration in circulation.