Liver targeting of catalase by cationization for prevention of acute liver failure in mice.
To achieve hepatic delivery of CAT for the prevention of CCl4-induced acute liver failure in mice, two types of cationized CAT derivatives, HMD- and ED-conjugated CAT, were developed. Slight structural changes occurred during cationization and the number of increased free amino groups was 3.1 in HMD-CAT and 13.6 in ED-CAT. 111In-cationized CAT derivatives showed an increased binding to HepG2 cells, and were rapidly taken up by the liver. H2O2-induced cytotoxicity in HepG2 cells was significantly prevented by preincubation of the cells with cationized CAT derivatives. A bolus intravenous injection of the cationized CAT derivatives reduced the hepatotoxicity induced by CCl4 in mice. The ED-CAT, which showed more rapid and greater binding to the liver than the HMD-CAT, exhibited more beneficial effects as far as all the parameters examined (serum GOT, GPT, LDH and hepatic GSH) were concerned, suggesting that a high degree of cationization is effective in delivering CAT to the liver to prevent CCl4-induced hepatotoxicity. These results suggest that cationized CAT derivatives are effective in preventing acute liver failure, and ED-based cationization is a suitable method for developing liver-targetable cationized CAT derivatives, because it provides CAT with a high degree of cationization and a high remaining enzymatic activity.
Ma
Shen-Feng
SF
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Nishikawa
Makiya
M
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Katsumi
Hidemasa
H
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Yamashita
Fumiyoshi
F
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.
Hashida
Mitsuru
M
Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: hashidam@pharm.kyoto-u.ac.jp.
D000818:Animals; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control*; D002374:Catalase / Q000008:administration & dosage* / Q000627:therapeutic use*; D002412:Cations / Q000737:chemistry; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D016503:Drug Delivery Systems; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D007205:Indium Radioisotopes; D007553:Isotope Labeling; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000517:prevention & control*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D016877:Oxidants / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000633:toxicity; D014018:Tissue Distribution
D002412:Cations; D016166:Free Radical Scavengers; D007205:Indium Radioisotopes; D016877:Oxidants; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002374:Catalase