Makiya Nishikawa

Kyoto University, Kioto, Kyōto, Japan

Are you Makiya Nishikawa?

Claim your profile

Publications (210)917.67 Total impact

  • [show abstract] [hide abstract]
    ABSTRACT: A novel polymeric prodrug of prostaglandin E1 (PGE1) was synthesized using lactosylated poly(l-glutamic hydrazide) (Lac-NH-PLGA) as a targetable carrier to hepatocytes. Poly(l-glutamic hydrazide) (PLGA-HZ) was prepared by reacting poly(γ-benzyl-l-glutamate) with hydrazine monohydrate, followed by coupling with lactose via a hydrazone linkage. Then the lactosylated PLGA-HZ was reduced by sodium cyanoborohydride (NaBH3CN) in order to make the linkage irreversible (Lac-NH-PLGA). Finally, PGE1 was bound to hydrazide moieties remaining in Lac-NH-PLGA without any condensing agent under weakly acidic conditions (pH 5) where PGE1 would be chemically most stable at room temperature (PGE1 conjugate). The PGE1 conjugate prepared was sufficiently water-soluble in spite of the hydrophobic nature of its backbone (-NH-CH-CO-) and PGE1 itself. After intravenous injection in mice, the [111In]PGE1 conjugate rapidly accumulated in the liver, whereas [111In]PLGA-HZ did not, suggesting the involvement of a galactose-specific mechanism in the uptake of the [111In]PGE1 conjugate. Fractionation of liver cells revealed that the [111In]PGE1 conjugate was preferentially taken up by liver parenchymal cells. The pharmacological activity was examined in mice with fulminant hepatitis induced by intraperitoneal injection of carbon tetrachloride. Intravenous injection of the PGE1 conjugate at a dose of 1 mg (0.065 mg PGE1)/kg effectively inhibited the increase in plasma glutamic pyruvic transaminase (GPT) activity compared with that of free PGE1 at a dose of 0.065 or 0.65 mg/kg. These results suggest that the PGE1 conjugate is an excellent prodrug for the treatment of fulminant hepatitis.
    Biochemical Pharmacology 01/2002; · 4.58 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Cationic liposomes and polymers have been accepted as effective non-viral vectors for gene delivery with low immunogenicity unlike viral vectors. However, the lack of organ or cell specificity sometimes hampers their application and the development of a cell-specific targeting technology for them attracts great interest in gene therapy. In this review, the potential of cell-specific delivery of genes with glycosylated liposomes or polymers is discussed. Galactosylated liposomes and poly(amino acids) are selectively taken up by the asialoglycoprotein receptor-positive liver parenchymal cells in vitro and in vivo after intravenous injection. DNA–galactosylated cationic liposome complexes show higher DNA uptake and gene expression in the liver parencymal cells in vitro than DNA complexes with bare cationic liposomes. In the in vitro gene transfer experiment, galactosylated liposome complexes are more efficient than DNA–galactosylated poly(amino acids) complexes but they have some difficulties in their biodistribution control. On the other hand, introduction of mannose residues to carriers resulted in specific delivery of genes to non-parenchymal liver cells. These results suggest advantages of these glycosylated carriers in cell-specific targeted delivery of genes.
    Advanced Drug Delivery Reviews 12/2001; · 12.89 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Our previous study demonstrated that the combination of mannosylated superoxide dismutase (Man-SOD) and succinylated catalase (Suc-CAT), both of which are designed to be targeted to liver nonparenchymal cells, is a promising approach to prevent the initial phase of hepatic ischemia/reperfusion injury induced by occlusion of the portal vein for 30 min followed by a 1-h reperfusion in mice. In this study, the preventive effects of these agents were examined on late-phase injury mediated by infiltrating neutrophils, a more severe condition than the initial one. Administration of Suc-CAT alone or with Man-SOD to mice undergoing hepatic ischemia/reperfusion significantly suppressed the expression of intercellular adhesion molecule-1 along the hepatic sinusoid and prevented neutrophil infiltration in the liver. Man-SOD and Suc-CAT also prevented the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase activities after reperfusion lasting 3 and 6 h. Histological evaluation of liver tissues confirmed the efficacy of this treatment, suggesting that these SOD and catalase derivatives have the ability to suppress neutrophil-induced hepatic injury. These results demonstrate that targeted delivery of antioxidant enzymes to liver nonparenchymal cells is a promising approach to reducing the reactive oxygen species produced by Kupffer cells and neutrophils infiltrating into the tissue. Since Suc-CAT is partially taken up by hepatocytes via a catalase-specific uptake mechanism, such a fraction could also be involved in its preventive effect against the injury.
    Journal of Pharmacology and Experimental Therapeutics 10/2001; 298(3):894-9. · 3.89 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: In vivo recognition of mannosylated proteins by hepatic mannose receptors and serum mannan-binding protein (MBP) was investigated in mice. After intravenous administration, all three different (111)In-mannosylated proteins were taken up mainly by liver, and uptake was saturated with increasing doses. (111)In-Man-superoxide dismutases and (111)In-Man(12)- and (111)In-Man(16)-BSA had simple dose-dependent pharmacokinetic profiles, whereas other derivatives ((111)In-Man(25)-, -Man(35)-, and -Man(46)-BSA and (111)In-Man-IgGs) showed slow hepatic uptake at <1 mg/kg. Purified MBP experiments in vitro indicated that these derivatives bind to MBP in serum after injection, which interferes with their hepatic uptake. To quantitatively evaluate these recognition properties in vivo, a pharmacokinetic model-based analysis was performed for (111)In-Man-BSAs, estimating some parameters, including the Michaelis-Menten constant of the hepatic uptake and the dissociation constant of MBP, which correlate to the affinity of Man-BSAs for mannose receptors and MBP, respectively. The dissociation constant of Man-BSA and MBP decreased dramatically with increasing density of mannose, but the Michaelis-Menten constant of hepatic uptake of Man-BSA was not so sensitive to the change in density. This suggests that the in vivo recognition of MBP has a stronger cluster effect than that of mannose receptors. Differences obtained here are due to the unique arrangement of carbohydrate recognition domains on each mannose-specific lectin available for mannosylated ligand recognition.
    AJP Gastrointestinal and Liver Physiology 06/2001; 280(5):G879-89. · 3.65 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: A series of pharmacokinetic studies following systemic or local administration for the development of delivery systems for gene drugs, such as plasmid DNA and oligonucleotides, are reviewed. The pharmacokinetics of gene drugs after intravenous injection into mice was evaluated based on clearance concepts. Pharmacokinetic analysis revealed that the overall disposition characteristics of the gene drug itself were determined by the physicochemical properties of its polyanionic DNA. Based on these findings, liver cell-specific carrier systems via receptor-mediated endocytosis were successfully developed by optimizing physicochemical characteristics. On the other hand, the pharmacokinetics of gene drugs after intratumoral injection were assessed in a tissue-isolated tumor perfusion system. The relationship between the physicochemical properties of gene drug delivery systems and intratumoral pharmacokinetics was determined and the therapeutic effect was also discussed in relation to pharmacokinetics. Collectively, it was demonstrated that a rational design of gene drug delivery systems that can control their in vivo disposition is possible by means of pharmacokinetic studies at whole body, organ and cellular levels.
    European Journal of Pharmaceutical Sciences 05/2001; 13(1):71-6. · 2.99 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: The roles of serum mannan binding protein (MBP) and the mannose receptor in the cellular uptake of mannosylated liposomes (Man-liposomes) by macrophages were studied. Man-liposomes were prepared by incorporating cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiomannosylethyl)amino)butyl)formamide (Man-C4-Chol) into small unilamellar long circulating liposomes consisting of cholesterol (Chol) and distearoyl phosphatidylcholine (DSPC). In the in vitro cellular uptake study with cultured mouse peritoneal macrophages, [(3)H]Man-liposomes were taken up to a great extent, whereas no significant uptake was observed for [(3)H]cholesterol and DSPC liposomes without Man-C4-Chol (Bare-liposomes). The uptake of [(3)H]Man-liposomes was dose- and temperature-dependent and inhibited by an excess of mannosylated bovine serum albumin, suggesting their specific uptake via membrane mannose receptor-mediated endocytosis. Furthermore, it was demonstrated that (111)In-MBP binds strongly to Man-liposomes based on the recognition of Man-C4-Chol and markedly enhanced their uptake by macrophages. These results are supported by confocal laser microscopic images. In addition, in vivo hepatic uptake of (111)In-MBP was enhanced by Man-liposomes. On the other hand, the uptake of Man-liposomes was significantly reduced by preincubation with serum and further with MBP-depleted serum suggesting inhibitory effects of serum proteins such as albumin on mannose receptor-mediated endocytosis. The involvement of serum-type MBP and membrane mannose receptors in the uptake of Man-liposomes is thus suggested.
    Biochimica et Biophysica Acta 04/2001; 1511(1):134-45. · 4.66 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To examine the potential utility of fucosylation of drug carriers for targeted drug delivery to Kupffer cells, the pharmacokinetics of (111)In-labeled fucosylated bovine serum albumin (Fuc-BSA) with different numbers of fucose residues (11, 16, 25, 31 or 41) was studied. After intravenous injection in mice, all (111)In-Fuc-BSAs were mainly delivered to the liver and their hepatic uptake became saturated when the dose was increased. Of these derivatives, only (111)In-Fuc41-BSA showed a slow plasma elimination at low doses, suggesting an interaction with blood components. Examination of binding conditions as well as electrophoretic analysis of the binding components indicated that the serum-type mannan binding protein (MBP) is responsible. Kupffer cells, which possess fucose receptors, showed the highest uptake of (111)In-Fuc41-BSA, followed by endothelial cells and hepatocytes. The hepatic uptake of (111)In-Fuc41-BSA was inhibited by co-injection of Gal42-BSA, but not by Man46-BSA. On the other hand, excess Fuc41-BSA inhibited the hepatic uptake of (111)In-Man46-BSA, while (111)In-Gal42-BSA did not: These findings suggest that not only the fucose receptors on Kupffer cells but also other lectins are involved in the biodistribution of Fuc-BSAs. To understand how the degree of fucose modification affects the binding affinity of Fuc-BSA with hepatic lectins and serum MBP, a pharmacokinetic analysis was performed based on a physiological model. The Michaelis constant of the hepatic uptake of (111)In-Fuc-BSA decreased with an increasing number of fucose units, and the intrinsic hepatic clearance of (111)In-Fuc25-, (111)In-Fuc31- and (111)In-Fuc41-BSAs was close to, or much greater than, the hepatic plasma flow rate, indicating efficient hepatic uptake of these derivatives. These results suggest that fucosylation is a potentially useful method making drug carriers selective for Kupffer cells, although extensive modification might result in retarded delivery due to binding to other lectins like MBP.
    Journal of Drug Targeting 02/2001; 9(5):341-51. · 2.77 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: To achieve hepatocyte-targeted in vivo gene expression, a carrier that controls both the tissue and intracellular distribution of DNA was designed and synthesized. A cationic polymer, poly(L-ornithine) (pOrn), was modified first with galactose, then with a fusigenic peptide (mHA2) to obtain Gal-pOrn-mHA2. When applied with Gal-pOrn-mHA2 to asialoglycoprotein receptor-positive cells, fluorescein-labeled DNA showed a diffuse profile, suggesting the release of DNA from endosomes and/or lysosomes by the carrier. Then the biodistribution and gene expression after intravenous injection of DNA complexes (10 microg DNA per mouse) were examined. After injection of [32P]DNA/Gal-pOrn-mHA2, about 60% of the radioactivity was recovered in the liver, mostly in parenchymal cells. A large amount (81 ng/g tissue) of transgene product (luciferase) was detected in the liver of mice injected with DNA/Gal-pOm-mHA2, which was 280-fold greater than that obtained with DNA/DOTMA:Chol liposomes (50 microg DNA). Prior administration of galactosylated albumin reduced the gene expression to 1/100, indicating the asialoglycoprotein receptor-mediated gene transfer in liver parenchymal cells, ie hepatocytes. The luciferase activity in hepatocytes contributed more than 95% of the total activity in all the tissues examined. Thus, hepatocyte-targeted in vivo gene expression was achieved by the intravenous injection of DNA complex with the multifunctional gene carrier.
    Gene Therapy 05/2000; 7(7):548-55. · 4.32 Impact Factor
  • [show abstract] [hide abstract]
    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.
    Pharmazie 04/2000; 55(3):202-5. · 0.96 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: A novel mannosylated cholesterol derivative, cholesten-5-yloxy-N-(4-((1-imino-2-beta-D-thiomannosyl -ethyl)amino)bu tyl) formamide (Man-C4-Chol), was synthesized in order to perform mannose receptor-mediated gene transfer with liposomes. Plasmid DNA encoding luciferase gene (pCMV-Luc) complexed with liposomes, consisting of a 6:4 mixture of Man-C4-Chol and dioleoylphosphatidylethanolamine (DOPE), showed higher transfection activity than that complexed with 3beta[N-(N', N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol)/DOPE(6:4) and N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA)/DOPE(1:1) liposomes in mouse peritoneal macrophages. The presence of 20 mM mannose significantly inhibited the transfection efficiency of pCMV-Luc complexed with Man-C4-Chol/DC- Chol/DOPE(3:3:4) and Man-C4-Chol/DOPE(6:4) liposomes. High gene expression of pCMV-Luc was observed in the liver after intravenously injecting mice with Man-C4-Chol/DOPE(6:4) liposomes, whereas DC-Chol/DOPE(6:4) liposomes only showed marked expression in the lung. The gene expression with Man-C4-Chol/DOPE(6:4) liposome/ DNA complexes in the liver was observed preferentially in the non-parenchymal cells and was significantly reduced by predosing with mannosylated bovine serum albumin. The gene expression in the liver was greater following intraportal injection. These results suggest that plasmid DNA complexed with mannosylated liposomes exhibits high transfection activity due to recognition by mannose receptors both in vitro and in vivo. Gene Therapy (2000) 7, 292-299.
    Gene Therapy 03/2000; 7(4):292-9. · 4.32 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Purpose. The purpose of this study is to elucidate the in vivo genetransfer for galactosylated liposomes containingcholesten-5-yloxy-N-(4-((1-imino-2--D-thiogalactosylethyl)amino)butyl)formamide(Gal-C4-Chol)in relation to lipid composition and charge ratio. Methods. Galactosylated cationic liposomes containingN-]1-(2,3-dioleyloxy)propyl]-n,n,n-trimethylammonium chloride(DOTMA),Gal-C4-Chol and cholesterol(Chol), and similar liposomes were prepared.Plasmid DNA complexed with a galactosylated liposome preparationwas injected intraportally into mice. The mice were sacrificed after 6hours. The tissues were subjected to luciferase assay. Results. A markedly higher gene expression in the liver followinginjection of plasmid DNA that has been complexed withDOTMA/Chol/Gal-C4-Chol(1:0.5:0.5) and DOTMA/Gal-C4-Chol(1:1)liposomes was observed. The effect was one order of magnitude higherthan naked DNA and DOTMA/Chol(1:1) liposomes. Pre-exposing withgalactosylated bovine serum albumin significantly reduced the hepaticgene expression. By comparison, the gene expression for galactosylatedcationic liposomes containing3[N-(N,N-dimethylaminoethane)-carbamoyl]cholesterol,Gal-C4-Chol and dioleoylphosphatidylethanolamine was 10 times lower.As far as the charge ratio of DOTMA/Chol/Gal-CA-Chol(1:0.5:0.5) liposomesto plasmid DNA(1.6-7.0) was concerned, complexes with charge ratiosof 2.3-3.1 produced maximal gene expression in the liver. Whereas,higher ratios resulted in enhanced expression in the lung. Conclusions. By optimizing lipid composition and charge ratio,galactosylated liposome/DNA complexes allow superior in vivo genetransfection in the liver via asialoglycoprotein receptor-mediatedendocytosis.
    Pharmaceutical Research 02/2000; 17(3):306-313. · 4.74 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To achieve mannose receptor-mediated, cell-specific, in vivo gene transfer by intravenous injection of plasmid DNA, mannosylated poly(L-lysine) (Man-PLL) was synthesized as a carrier molecule, and mixed with a plasmid DNA encoding chloramphenicol acetyltransferase (CAT) gene to form DNA/Man-PLL complex. The particle size and zeta potential of DNA/Man-PLL (prepared at 1:0.7 on a weight basis) were determined to be 220 nm and +12 mV, respectively. The pharmacokinetics of the DNA/Man-PLL complex was assessed in mice using 32P-labeled DNA ([32P]DNA). After intravenous injection of [32P]DNA/Man-PLL, the radioactivity in plasma fell rapidly and was recovered mainly in the liver nonparenchymal cells. The amount in the liver reached more than 80% of the dose. Radioactivity observed in kidney, lung, and spleen was very low compared to that in the liver. Then, the in vivo gene expression after intravenous injection of DNA/Man-PLL was examined by a CAT assay. Highest CAT activity was detected in the liver, but no activity was detected in the lung, kidney, and spleen. These results clearly indicate that a cell-specific gene delivery system can be developed by regulating the biodistribution of DNA/carrier complex through the control of its physicochemical properties.
    Journal of Drug Targeting 02/2000; 8(1):29-38. · 2.77 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The rapid clearance from plasma and the limited uptake of superoxide dismutase (SOD) in the liver hampers the effectiveness of this enzyme in liver diseases. We therefore compared the pharmacokinetics and in vivo efficacy of SOD with two modified forms of this protein: SOD coupled to the copolymer DIVEMA and mannosylated-SOD. Reactive oxygen scavenging activity of SOD conjugates was tested in livers of bile duct ligated rats. Intrahepatic production of reactive oxygen species (ROS) and neutrophil infiltration were studied immunohistochemically and related to the organ and cellular distribution of radiolabeled SOD conjugates. Native SOD was rapidly cleared from the circulation and accumulated in renal tubuli. The enzyme had no effect on the intrahepatic ROS production. Covalent attachment of SOD to DIVEMA yielded a polyanionic conjugate with a prolonged elimination half-life compared to native SOD. In contrast to native SOD, DIVEMA-SOD was taken up by the liver via scavenger receptors. Mannosylation of SOD (Man-SOD) resulted in a conjugate that was rapidly cleared from the blood. This Man-SOD was taken up by non-parenchymal liver cells. The pharmacokinetics of SOD and its derivatives were similar in normal and bile duct ligated rats. Efficacy studies with Man-SOD revealed only a slight decrease in intrahepatic ROS production. However, DIVEMA-SOD exhibited a potent inhibitory effect on ROS production in the liver. Nearly complete ROS-scavenging activity was observed in the portal areas. Considering the prolonged half-life, the increased delivery of SOD to the target cells, and the concomitant increased effectiveness, application of DIVEMA-SOD seems a promising new approach to attenuate intrahepatic inflammatory processes.
    Journal of Hepatology 01/2000; 31(6):1034-43. · 9.86 Impact Factor
  • [show abstract] [hide abstract]
    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. 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 PGE1 conjugate synthesized with activated PGE1 by 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, we next conjugated PGE1 to galactosylated poly-(l-glutamic acid) hydrazide (Gal-HZ-PLGA) in which PGE1 was easily coupled to Gal-HZ-PLGA via a hydrazone bond in weak acidic solution (pH 5) at room temperature. The PGE1-Gal-HZ-PLGA conjugate labeled with [111In] or [3H]PGE1 rapidly accumulated in the liver parenchymal cells. In addition, the PGE1 conjugate effectively inhibited the increase of the 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.
    Journal of Controlled Release 12/1999; · 7.63 Impact Factor
  • Makiya Nishikawa, Mitsuru Hashida
    [show abstract] [hide abstract]
    ABSTRACT: To achieve an optimal chemotherapy or gene therapy against tumors or to realize rational design of delivery systems for cancer therapy, pharmacokinetic information in tumor should be obtained. A tissue-isolated tumor preparation is a useful experimental system to investigate the intratumoral disposition of drugs, carriers, and their complexes. The disposition of drugs in the solid tumor was analyzed in this system after intraarterial infusion (systemic route) or by intratumoral injection (topical route). Here the results of low-molecular weight drugs, their macromolecular prodrugs, lipid carriers like fat emulsions and liposomes, and plasmid DNA and its complexes, are addressed. Pharmacokinetic analyses in the tumor clearly indicate that the intratumoral fate of drugs and delivery systems are determined by (i) the anatomical and physiological properties of the tissue and (ii) the physicochemical characteristics of drugs and delivery systems such as molecular weight, size, lipophilicity, and electrical charge. These approaches are useful for designing and developing optimized drug delivery systems.
    Advanced drug delivery reviews 12/1999; · 11.96 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: To study the mechanisms of the hepatic disposition of polystyrene microspheres (MS), effects of serum on their hepatic disposition characteristics were investigated for MSs with particle sizes of 50 nm (MS-50) and 500 nm (MS-500) by isolated liver perfusion experiments. It was revealed that serum in the perfusate inhibited and promoted the hepatic disposition of MS-50 and MS-500 at 37°C, respectively. However, pre-heating at 56°C or pre-treatment with anti-C3 antibody of serum reduced the promotive effect of serum on the hepatic uptake of MS-500, suggesting that the complement system should be involved as opsonins for the hepatic uptake of MS-500. Hepatic disposition of both MSs at 4°C was reduced by the addition of serum into the perfusate, which could be ascribed to the reduction of the surface hydrophobicity of MSs due to the adsorption of serum proteins onto the surface of MSs and to resultant decrease in non-specific disposition to the liver. From these results, serum was found to function both as the opsonin to enhance the hepatic uptake of MSs and as the inhibitor by reducing non-specific interaction between MSs and the plasma membrane. Whether serum promotes or inhibits the hepatic disposition of MSs would be dependent on the particle sizes of MSs.
    Journal of Controlled Release 10/1999; · 7.63 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: A polymeric prodrug of prostaglandin E(1) (PGE(1)) 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(gamma-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. (111)In-labeled galactosylated poly(L-glutamic acid hydrazide) ((111)In-Gal-HZ-PLGA) rapidly accumulated in the liver in a dose-dependent manner, whereas (111)In-poly(L-glutamic acid hydrazide) did not, indicating the involvement of a galactose-specific mechanism in the uptake of (111)In-Gal-HZ-PLGA. Fractionation of liver cells revealed that (111)In-Gal-HZ-PLGA was preferentially taken up by liver parenchymal cells. After being taken up by the liver, (111)In-Gal-HZ-PLGA was gradually degraded, and radioactive metabolites with low molecular weight were detected within 10 min after injection. Then, PGE(1) or [(3)H]PGE(1) was coupled to Gal-HZ-PLGA via a hydrazone bond under mild conditions to obtain PGE(1) conjugate. After i.v. injection, [(3)H]PGE(1) conjugate was rapidly taken up by the liver (more than 80% of the dose). After injection of the conjugate, (3)H 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 [(3)H]PGE(1). Finally, its pharmacological activity was examined in mice with fulminant hepatitis induced by peritoneal injection of carbon tetrachloride. The i.v. injection of PGE(1) conjugate at a dose of 1 mg (0.074 mg PGE(1))/kg effectively inhibited the increase of plasma glutamic pyruvic transaminase activity, whereas twice this dose (0.15 mg/kg) of free PGE(1) had little effect. These results suggest that the PGE(1) conjugate is an excellent polymeric prodrug of PGE(1) for hepatitis therapy.
    Journal of Pharmacology and Experimental Therapeutics 10/1999; 290(3):1242-9. · 3.89 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The effect of radiolabeling liver-specific proteins on the in vivo disposition of radioactivity was investigated. The suitability of 111In and 125I as radiolabels for protein disposition studies in vivo was examined. Galactosylated and cationized bovine serum albumin were labeled with either 125I by the chloramine-T method or 111In, using 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-BZ-EDTA) or diethylenetriaminepentaacetic acid (DTPA) as bifunctional chelating agents (BCAs) and administered intravenously to rats. 125I radioactivity disappeared rapidly from the liver with subsequent excretion in the urine and bile, mainly in the TCA soluble fraction. 111In-associated radioactivity, on the other hand, remained in the hepatic tissue in considerably higher amounts during the experiment and was excreted in the bile and urine to a lower extent when compared with 125I. When the effect of BCA on excretion of 111In radioactivity was compared, no significant differences were observed in the urinary clearances. However, biliary excretion was significantly higher for 111In-SCN-BZ-EDTA-bound radioactivity. In conclusion, when compared with 125I, 111In labeling seems to more accurately characterize the in vivo distribution of liver-targeted proteins after their iv administration in rats and allows a more accurate pharmacokinetic evaluation to be performed.
    Journal of Pharmaceutical Sciences 07/1999; 88(6):577-85. · 3.13 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Four types of bovine liver catalase (CAT) derivatives, succinylated (Suc-CAT), galactosylated (Gal-CAT), mannosylated (Man-CAT), and polyethylene glycol conjugate (PEG-CAT), were synthesized and their pharmacokinetics and therapeutic potential in a hepatic ischemia/reperfusion injury model were studied in mice. About 90% of the CAT enzymatic activity was retained after chemical modification. Biodistribution studies showed that 111indium (111In)-Gal-CAT accumulated selectively in the liver parenchymal cells as 111In-CAT, whereas an increased amount of 111In-Suc-CAT and 111In-Man-CAT was delivered to liver nonparenchymal cells. 111In-PEG-CAT exhibited prolonged retention in plasma. Pharmacokinetic analysis revealed that the hepatic uptake clearances of 111In-Suc-CAT, 111In-Gal-CAT, and 111In-Man-CAT were much greater than that of 111In-CAT, whereas that of 111In-PEG-CAT was very small. In the ischemia/reperfusion injury model, in which hepatic injury was induced by occlusion of the portal vein for 30 min followed by 1 h reperfusion, the elevation of plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels was slightly inhibited by treatment with native CAT or Gal-CAT. PEG-CAT was less potent. In contrast, Suc-CAT and Man-CAT effectively suppressed the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase. Coinjection of mannosylated superoxide dismutase marginally improved the inhibitory effects of CAT derivatives. These results demonstrate that targeted CAT delivery to liver nonparenchymal cells via chemical modification is a promising approach to prevent hepatic injuries caused by reactive oxygen species. The potential usefulness of combining of CAT and superoxide dismutase derivatives is also demonstrated.
    Journal of Pharmacology and Experimental Therapeutics 06/1999; 289(2):1176-84. · 3.89 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The in vivo disposition of polystyrene microsphere (MS) with the particle size of 50 nm (MS-50) or 500 nm (MS-500) was characterized after intravenous administration to rats. A rapid elimination from systemic circulation was observed for both MSs. Tissue distribution of MS-50 and MS-500 at 1 h after intravenous injection indicated that both MSs were exclusively distributed to liver and that small but significant amounts of MS-50 and MS-500 were also distributed to lung and spleen, respectively. To investigate the intrahepatic distribution of MS, liver was separated into liver parenchymal cells (PC) and non-parenchymal cells (NPC) at 1 or 6 h after intravenous administration. The contribution of each cell fraction was dependent on both the size of MS and the time after administration. Furthermore, by separating the NPC into endothelial cells and Kupffer cells using a centrifugal elutriation method, their contribution was also evaluated. For both MSs, Kupffer cells were recognized to be mostly responsible for the hepatic uptake, although a significant amount of MS-50 (about 28% of total uptake) was taken up by PC. On the other hand, there was little contribution of PC (about 5%) to the hepatic uptake of MS-500. The endothelial cells were contributed larger to the uptake of MS-500 (about 24%) than that of MS-50 (13%).
    Journal of Controlled Release 06/1999; · 7.63 Impact Factor

Publication Stats

3k Citations
117 Downloads
917.67 Total Impact Points

Institutions

  • 1992–2014
    • Kyoto University
      • • Division of Pharmaceutical Sciences
      • • Graduate School of Pharmaceutical Sciences / Faculty of Pharmaceutical Sciences
      Kioto, Kyōto, Japan
  • 2010
    • Doshisha Women's College of Liberal Arts
      Kioto, Kyōto, Japan
  • 2007
    • Kyoto Pharmaceutical University
      • Laboratory of Analytical and Bioinorganic Chemistry
      Kioto, Kyōto, Japan
  • 2005
    • University of Kansas
      Lawrence, Kansas, United States
  • 1999
    • Kyoto Prefectural University of Medicine
      • Department of Surgery
      Kioto, Kyōto, Japan
    • Okayama University
      • Faculty of Pharmaceutical Science
      Okayama, Okayama, Japan
  • 1993
    • Setsunan University
      • Faculty of Pharmaceutical Sciences
      Ōsaka, Ōsaka, Japan