Abstract
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.
Footnotes
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Send reprint requests to: Dr. Mitsuru Hashida, Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidasimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. E-mail:hashidam{at}pharm.kyoto-u.ac.jp
- Abbreviations:
- PGE1
- prostaglandin E1
- PLGA
- poly(l-glutamic acid)
- Gal-HZ-PLGA
- galactosylated poly(l-glutamic acid hydrazide)
- PGE1conjugate
- prostaglandin E1 prodrug using Gal-HZ-PLGA as a carrier
- DTPA anhydride
- diethylenetriamine-N,N,N′,N",N"-pentaacetic dianhydride
- GPT
- glutamic pyruvic transaminase
- DP
- degree of polymerization
- IME
- 2-imino-2-methoxyethyl-1
- AUC
- area under the plasma concentration-time curve
- CLtotal
- total body clearance
- CLliver
- clearance for liver
- Received February 8, 1999.
- Accepted April 27, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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