Vol. 290, Issue 3, 1242-1249, September 1999

Development of a Hepatocyte-Specific Prostaglandin E₁ Polymeric Prodrug and Its Potential for Preventing Carbon Tetrachloride-Induced Fulminant Hepatitis in Mice

Ken Akamatsu, Yasuomi Yamasaki, Makiya Nishikawa, Yoshinobu Takakura and Mitsuru Hashida

Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan

A polymeric prodrug of prostaglandin E₁ (PGE₁) was synthesized using galactosylated poly(L-glutamic acid hydrazide) (Gal-HZ-PLGA) as a biodegradable and targetable carrier to hepatocytes. Poly(L-glutamic acid hydrazide) was prepared by reacting poly(-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.