Design of polymeric prodrugs of prostaglandin E1 having galactose residue for hepatocyte targeting

Abstract

Based on the relationship between in vivo disposition of macromolecules and their physicochemical and biological characteristics obtained through clearance concept-based pharmacokinetic analysis, polymeric prodrugs of prostaglandin E1(PGE1) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. First poly-l-lysine (PLL) and poly-l-glutamic acid (PLGA) with an ethylenediamine (ED) spacer were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated derivatives. After intravenous injection in mice, Gal-ED-PLGA was selectively taken up by the liver parenchymal cells via receptor-mediated endocytosis, while Gal-PLL accumulated in the liver as well as PLL mostly due to electrostatic interaction. Although Gal-ED-PLGA showed good targeting efficacy, its PGE1 conjugate synthesized with activated PGE1 by carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE1 during conjugation and lack of release in the tissue. In order to overcome these problems, we next conjugated PGE1 to galactosylated poly-(l-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE1 was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells. In addition, the PGE1 conjugate effectively inhibited the increase of the GPT level in plasma, while free PGE1 indicated no therapeutic efficacy even at more than ten times higher doses, in carbon tetrachloride-induced hepatitis mice. These findings suggest potentials of polymeric targeting systems of PGE1 to hepatocyte utilizing galactose recognition.