title: Design of polymeric prodrugs of PGE1 for cell-specific hepatic 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. Although galactosylated poly-L-glutamic acid with a ethylene diamine (ED) spacer (Gal-ED-PLGA) showed good targeting efficacy in mice, its PGE1 conjugate synthesized by the 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, PGE1 was conjugated to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) via hydrazone bond. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells after intravenous injection. In addition, PGE1 conjugate effectively inhibited the increase of 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Japan. hashidam@pharm.kyoto-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Hashida
authors.forename: K
authors.initials: K
authors.lastname: Akamatsu
authors.forename: M
authors.initials: M
authors.lastname: Nishikawa
authors.forename: F
authors.initials: F
authors.lastname: Yamashita
authors.forename: H
authors.initials: H
authors.lastname: Yoshikawa
authors.forename: Y
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000208:Acute Disease; D000527:Alprostadil / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002252:Carbon Tetrachloride Poisoning / Q000517:prevention & control; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control; D015195:Drug Design; D007205:Indium Radioisotopes; D019344:Lactic Acid; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011107:Polylysine; D011108:Polymers; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D007205:Indium Radioisotopes; D011108:Polymers; D011355:Prodrugs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011107:Polylysine; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000527:Alprostadil