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Increased liver uptake of liposomes and improved targeting efficacy by labeling with asialofetuin in rodents

To improve liposome‐directed therapy of liver disease and gene delivery, it would be beneficial to selectively target hepatocytes. For this purpose, conventional liposomes (CL) were labeled with asialofetuin (AF), an asialoglycoprotein. The biodistribution of AF‐labeled liposomes (AF‐L) in mice and their incorporation into rat hepatocytes, and their potential use in acute liver injury, were investigated. AF‐L displayed a quicker plasma clearance than CL, and 25.4%, 2.7%, and 1.2% of the injected dose remained in the plasma versus 47.0%, 26.1%, and 9.5% of CL, respectively at 2, 4, and 20 hours after the injection. Total liver uptake of AF‐L (73% ± 3.9%) was markedly higher (P < .005) than CL (16.5% ± 1.8%) 4 hours after the injection. Liposomal radioactivity (cpm/mg) was greatly enhanced in the liver (11‐fold) during the first 4 hours after the administration of 14C‐AF‐L, and was much higher than in 14C‐CL–injected mice (1.5‐fold). In vitroncubation of isolated rat hepatocytes with 14C‐AF‐L or intravenous injection of 14C‐AF‐L in rats resulted in higher hepatocyte‐bound radioactivity compared with 14C‐CL (P < .01‐.005). AF‐L–associated 1,1′‐dilinoleyl‐3,3,3′,3′‐tetramethylindocarbocyanine perchlorate (DiI) fluorescent signals were not only located in Kupffer cells, but also in hepatocytes, in which bile canaliculus networks were imaged. Intravenous administration of vitamin E (VE)–associated CL (VE‐CL, 1 mg/mouse) significantly lowered alanine transaminase (ALT) levels in CCl4 ‐treated mice (196 ± 79 vs. 2,107 ± 235 U/mL; P < .01). The ALT level in CCl4 + VE‐AF‐L group was decreased to 38 ± 16 units/mL, which was significantly lower than the CCl4 + VE‐CL group (P < .05). In conclusion, labeling liposomes with AF led to a shortened liposome plasma half‐life and greatly enhanced uptake of AF‐L liposome by the liver. The enhanced uptake resulted from an increased incorporation of hepatocytes with AF‐L liposomes. VE‐associated AF liposomes further improved the protective effect of VE liposomes on CCl4 ‐induced acute liver injury in mice. Preferential hepatocyte incorporation of AF‐L liposomes suggests a useful hepatocyte‐targeting approach for drug delivery and gene transfection.