PURPOSE: The effect of liposome size and cholesterol (CH) content on the pharmacokinetics of liposomes was investigated in rats. METHODS: The pharmacokinetics of liposomes was examined using 5(6)-carboxyfluorescein (CF) as an aqueous phase marker. The extent of complement activation (ECA) was also measured by the release of CF from liposomes in serum. RESULTS: Both the size and the CH content influenced the mean residence time, total body clearance, and the hepatic uptake clearance (CLh) of liposomes. The increase of the size of liposomes increased the CLh at each CH content. There was no CH dependency of CLh in small liposomes (200 nm in diameter), although the CLh increased with the increase in the CH content in large (800 nm) and medium (400 nm) liposomes. A significant interaction effect was observed between liposome size and the CH content on CLh according to the analysis of variance. The good correlation between CLh and ECA indicated the role of complements as opsonins in enhancing the hepatic uptake of liposomes. The interaction effect between the size and CH content on CLh was explained principally by the product of the size and CH content. CONCLUSIONS: A synergistic effect was observed between the size and the CH content on CLh. An underlying hypothesis of the synergistic effect was postulated based on the size dependent recognition of liposomes by complement system.
PURPOSE: The effect of liposome size and cholesterol (CH) content on the pharmacokinetics of liposomes was investigated in rats. METHODS: The pharmacokinetics of liposomes was examined using 5(6)-carboxyfluorescein (CF) as an aqueous phase marker. The extent of complement activation (ECA) was also measured by the release of CF from liposomes in serum. RESULTS: Both the size and the CH content influenced the mean residence time, total body clearance, and the hepatic uptake clearance (CLh) of liposomes. The increase of the size of liposomes increased the CLh at each CH content. There was no CH dependency of CLh in small liposomes (200 nm in diameter), although the CLh increased with the increase in the CH content in large (800 nm) and medium (400 nm) liposomes. A significant interaction effect was observed between liposome size and the CH content on CLh according to the analysis of variance. The good correlation between CLh and ECA indicated the role of complements as opsonins in enhancing the hepatic uptake of liposomes. The interaction effect between the size and CH content on CLh was explained principally by the product of the size and CH content. CONCLUSIONS: A synergistic effect was observed between the size and the CH content on CLh. An underlying hypothesis of the synergistic effect was postulated based on the size dependent recognition of liposomes by complement system.