A polymeric prodrug of prostaglandin E1 (PGE1) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (GalHZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(γ-benzyl-L-glutamate) with hydrazine monohydrate, followed by reaction with 2-imino-2-methoxyethyl-1- thiogalactosides to obtain Gal-HZ-PLGA after i.v. injection. 111In-labeled galactosylated poly(L-glutamic acid hydrazide) (111In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas 111In-poly(L- glutamic acid hydrazide) did not, indicating the involvement of a galactose- specific mechanism in the uptake of 111In-Gal-HZ-PLGA. Fractionation of liver cells revealed that 111In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, 111In-Gal-HZ- PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE1 or [3H]PGE1 was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE1 conjugate. After i.v. injection, [3H]PGE1 conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, 3H radioactivity remained in the liver, representing about 70% of the dose, even at 24 h, whereas little radioactivity remained in the organ at 1 h after the injection of free [3H]PGE1. Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE1 conjugate at a dose of 1 mg (0.074 mg PGE1/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE1 had little effect. These results suggest that the PGE1 conjugate is an excellent polymeric prodrug of PGE1 for hepatitis therapy.
|ジャーナル||Journal of Pharmacology and Experimental Therapeutics|
|出版物ステータス||Published - 1 9 1999|