title: Design of polymeric prodrugs of prostaglandin E(1) having galactose residue for hepatocyte 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 E(1)(PGE(1)) were designed stepwise and evaluated on their targeting and therapeutic efficiencies. First poly-L-lysine (PLL) and poly-L-glutamic acid (PLGA) with an ethylenediamine (ED) spacer were modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated derivatives. After intravenous injection in mice, Gal-ED-PLGA was selectively taken up by the liver parenchymal cells via receptor-mediated endocytosis, while Gal-PLL accumulated in the liver as well as PLL mostly due to electrostatic interaction. Although Gal-ED-PLGA showed good targeting efficacy, its PGE(1) conjugate synthesized with activated PGE(1) by carbonyldiimidazole method failed to show therapeutic effects probably due to inactivation of PGE(1) during conjugation and lack of release in the tissue. In order to overcome these problems, we next conjugated PGE(1) to galactosylated poly-(L-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE(1) was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE(1)-Gal-HZ-PLGA conjugate labeled with [(111)In] or [(3)H]PGE(1) rapidly accumulated in the liver parenchymal cells. In addition, the PGE(1) conjugate effectively inhibited the increase of the GPT level in plasma, while free PGE(1) 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 PGE(1) to hepatocyte utilizing galactose recognition.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
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: Y
authors.initials: Y
authors.lastname: Takakura
mesh_terms: D000527:Alprostadil / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001673:Biodegradation, Environmental; D002240:Carbohydrate Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D005690:Galactose / Q000737:chemistry; D006031:Glycosylation; D019344:Lactic Acid / Q000737:chemistry; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D051379:Mice; D008969:Molecular Sequence Data; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011107:Polylysine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology*; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: D011108:Polymers; D011355:Prodrugs; D014867:Water; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011107:Polylysine; D011100:Polyglycolic Acid; D019344:Lactic Acid; D000527:Alprostadil; D005690:Galactose