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Increased liver uptake of liposomes and improved targeting efficacy by labeling with asialofetuin in rodents
Author(s) -
Wu Jian,
Liu Pei,
Zhu JianLiang,
Maddukuri Sivaramaiah,
Zern Mark A.
Publication year - 1998
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510270319
Subject(s) - hepatocyte , liposome , biodistribution , asialoglycoprotein receptor , chemistry , pharmacology , alanine transaminase , microbiology and biotechnology , medicine , endocrinology , in vitro , biology , biochemistry
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 14 C‐AF‐L, and was much higher than in 14 C‐CL–injected mice (1.5‐fold). In vitro ncubation of isolated rat hepatocytes with 14 C‐AF‐L or intravenous injection of 14 C‐AF‐L in rats resulted in higher hepatocyte‐bound radioactivity compared with 14 C‐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 CCl 4 ‐treated mice (196 ± 79 vs. 2,107 ± 235 U/mL; P < .01). The ALT level in CCl 4 + VE‐AF‐L group was decreased to 38 ± 16 units/mL, which was significantly lower than the CCl 4 + 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 CCl 4 ‐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.