PT  - JOURNAL ARTICLE
AU  - Ken Akamatsu
AU  - Yasuomi Yamasaki
AU  - Makiya Nishikawa
AU  - Yoshinobu Takakura
AU  - Mitsuru Hashida
TI  - Development of a Hepatocyte-Specific Prostaglandin E<sub>1</sub>Polymeric Prodrug and Its Potential for Preventing Carbon Tetrachloride-Induced Fulminant Hepatitis in Mice
DP  - 1999 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1242--1249
VI  - 290
IP  - 3
4099  - http://jpet.aspetjournals.org/content/290/3/1242.short
4100  - http://jpet.aspetjournals.org/content/290/3/1242.full
SO  - J Pharmacol Exp Ther1999 Sep 01; 290
AB  - 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(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, whereas111In-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]PGE1was 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. The American Society for Pharmacology and Experimental Therapeutics