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Hepatic Targeting Of Drugs And Proteins By Chemical Modification

M. Hashida, M. Nishikawa, Y. Takakura
Published 1995 · Chemistry

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Abstract The effectiveness of several approaches to hepatic targeting of drugs and proteins was compared with regard to various aspects. Receptor-mediated endocytosis of macromolecules with sugar moieties by parenchymal or nonparenchymal cells, scavenger receptor-mediated endocytosis of polyanions by non-parenchymal cells, and universal electrostatic interaction of polycations were characterized by pharmacokinetic analysis at the whole body level or in liver perfusion experiments employing albumin as a model macromolecule. Based on the results obtained, asialoglycoprotein receptor-mediated endocytosis was employed for the targeting of vitamin K 5 and cytosine arabinoside using poly L-glutamic acid and carboxymethyl-dextran, respectively, as backbones, and specific delivery of more than 70% of dose was achieved for both drugs after intravenous injection. Similar approaches were applied to superoxide dismutase (SOD), and superior therapeutic effect against hepatic injury induced by ischemia/reperfusion was observed in mannosylated SOD. The effect of the extent of modification with sugar moieties on hepatic targeting of proteins is also discussed.
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