Targeted delivery of drugs and proteins to the liver via receptor-mediated endocytosis

Targeting of drugs and proteins to the liver via the asialoglycoprotein receptor was investigated in mice. Carboxymethyl-dextran (CMD), carboxymethyl-amylose (CMA), and poly-L-glutamic acid (PLGA) were modified with 2-imino-2-methoxyethyl (IME)-thiogalactosides to obtain galactosylated derivatives as carriers of drugs with low-molecular weights. Proteins were targeted to the liver by direct attachment of galactose moieties. Pharmacokinetic analysis clearly showed that galactosylated derivatives were taken up by the liver depending on the molecular weight and configuration of macromolecules, the number of galactose residues, and the administered dose. Based on the obtained results, we attempted to selectively deliver vitamin K-5, which acts as a coagulant in the liver. Galactosylated PLGA (Gal-PLGA) possessing 18 galactose residues was selected as a hepatotropic carrier since it was efficiently accumulated and gradually degraded in the liver after intravenous injection. The attachment of vitamin K-5 did not alter the distribution properties of Gal-PLGA, and vitamin K-5 was successfully delivered to the liver by the conjugation. The anti-hemorrhagic activity of the conjugate was assayed after intravenous injection in mice treated with warfarin. Vitamin K-5 conjugated with Gal-PLGA showed coagulant activity at any periods studied after intravenous injection, while free vitamin K-5 only showed the activity at 4 h after administration. These results indicate the usefulness of galactosylated macromolecules as hepatotropic carriers of drugs whose site of action is in the liver.