Biodistribution characteristics of galactosylated emulsions and incorporated probucol for hepatocyte-selective targeting of lipophilic drugs in mice.
OBJECTIVE
Galactosylated emulsions containing cholesten-5-yloxy-N-(4-((1-imino-2-D-thiogalactosylethyl)amino)butyl)formamide (Gal-C4-Chol) as a "homing device" were developed for hepatocyte-selective drug targeting. The targeting efficiency of galactosylated emulsions was evaluated by a distribution study in mice.


METHODS
Soybean oil/EggPC/cholesterol (Chol) (weight ratio, 70:25: 5) (bare) emulsions and soybean oil/EggPC/Gal-C4-Chol (weight ratio, 70:25:5) (Gal) emulsions were prepared and labeled with [3H]cholesteryl hexadecyl ether (CHE). [14C]probucol as a model lipophilic drug was incorporated in the emulsions or EggPC/Chol/Gal-C4-Chol (Gal) liposomes. Their tissue and intrahepatic distribution were evaluated following intravenous injection in mice.


RESULTS
After intravenous injection, Gal-emulsions were rapidly eliminated from the blood and accumulated in the liver, in contrast to the bare-emulsions. The liver uptake clearance of Gal-emulsions was 3.2- and 1.2-times greater than that of bare-emulsions and Gal-liposomes, respectively. The uptake ratio in liver parenchymal cells (PC) and nonparenchymal cells (NPC) of Gal-emulsions was higher than that of Gal-liposomes, being 7.4 and 3.0, suggesting that Gal-emulsions are an effective PC-selective carrier. The hepatic uptake of Gal-emulsions, but not that of bare-emulsions, was significantly inhibited by the pre-dosing of not only lactoferrin but also Gal-liposomes, suggesting asialoglycoprotein receptor-mediated endocytosis. Furthermore, [14C]probucol incorporated in Gal-emulsions was efficiently delivered to the liver compared with Gal-liposomes.


CONCLUSIONS
Gal-emulsions have been proven to be an alternative carrier for hepatocyte-selective drug targeting.
Ishida
Emi
E
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Managit
Chittima
C
Kawakami
Shigeru
S
Nishikawa
Makiya
M
Yamashita
Fumiyoshi
F
Hashida
Mitsuru
M
D000818:Animals; D002250:Carbon Radioisotopes; D002627:Chemistry, Physical / Q000379:methods; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004337:Drug Carriers / Q000378:metabolism / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods*; D004530:Egg Yolk / Q000737:chemistry / Q000378:metabolism; D004655:Emulsions / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D005690:Galactose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D007564:Japan; D008081:Liposomes / Q000138:chemical synthesis / Q000145:classification / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010316:Particle Size; D011341:Probucol / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D012995:Solubility / Q000187:drug effects; D013024:Soybean Oil / Q000378:metabolism / Q000494:pharmacology; D013678:Technology, Pharmaceutical / Q000379:methods; D014018:Tissue Distribution / Q000187:drug effects* / Q000502:physiology; D014316:Tritium
D002250:Carbon Radioisotopes; D004337:Drug Carriers; D004655:Emulsions; D008081:Liposomes; D014316:Tritium; D013024:Soybean Oil; D002784:Cholesterol; D011341:Probucol; D005690:Galactose