Kaneto Uekama

Sojo University, Kumamoto, Kumamoto, Japan

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Publications (422)598.68 Total impact

  • Asian Journal of Pharmaceutical Sciences 11/2015; DOI:10.1016/j.ajps.2015.11.097
  • Daisuke Iohara · Makoto Anraku · Kaneto Uekama · Fumitoshi Hirayama ·

    Asian Journal of Pharmaceutical Sciences 11/2015; DOI:10.1016/j.ajps.2015.10.036
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    ABSTRACT: Objectives20S-protopanaxadiol 20-O-β-D-glucopyranoside (compound K), a metabolite of ginsenoside, is only sparingly soluble in water. The aim of this study was to improve the low solubility, slow dissolution rate and low oral bioavailability of compound K by forming an inclusion complex with γ-cyclodextrin (γ-CyD), and to compare the results with those of β-CyD complex.Methods The interactions of compound K with β and γ-CyDs were studied by the solubility method and proton nuclear magnetic resonance spectroscopy. Solid forms of compound K/CyD complexes with different molar ratios were prepared by the kneading method, and the resulting complex was characterized by powder X-ray diffractometry. The dissolution rate of the complexes was measured by the rotary disk method. In-vivo absorption studies in rats were carried out, and the serum level of compound K, after its oral administration, was measured by a liquid chromatography-tandem mass spectrometry system.Key findingsγ-CyD markedly improved the low solubility of compound K at lower CyD concentrations (<0.03 M), whereas the solubility was decreased at higher concentrations (>0.06 m). The enhancement in solubility by γ-CyD at a lower concentration was much higher than the corresponding values for β-CyD. The apparent 1:1 stability constant (1.5 × 105 m−1) for the γ-CyD complex was 18-fold larger than that (8.2 × 103 m−1) of the β-CyD complex. The dissolution rate of the 1:1 compound K/γ-CyD complex was faster than that for the 1:3 (guest : host) complex. These results suggest that the dissolution rate of the 1:1 complex, in which the drug is partially included, was faster than that of the 1:3 complex, in which the drug was completely included, due to the higher solubility and amorphous property of the former complex compared with the properties of the latter complex. The fast dissolution of the γ-CyD complex was reflected in the maximum plasma level (Cmax) of the drug and the time (Tmax) to reach the maximum plasma level after its oral administration to rats.Conclusions The effect of γ-CyD on enhancing the solubility of compound K is much higher than that for the β-CyD complex, and the dissolution rate of the guest when it is partially included in the γ-CyD is faster the corresponding value when it is completely included in the cavity.
    09/2015; DOI:10.1111/jphp.12468
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    ABSTRACT: Oxidative stress is known to be involved in the pathogenesis of chronic renal failure (CRF). In this study, the effect of cyclodextrins (CDs) on oxidative stress and CRF was investigated using 5/6 nephrectomized rats as model animals. CRF model rats were divided into five groups and treated for 8 weeks as follows: control, α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-CD (HP-β-CD). Blood was collected from the rats after 4 and 8 weeks for an analysis of renal function and oxidative stress tests were carried out. An oral administration of HP-β-CD over an 8-week period resulted in a significant decrease in serum indoxyl sulphate, creatinine and urea nitrogen levels, compared with the other CDs. The ingestion of HP-β-CD also resulted in an increase in antioxidant potential, compared with the other CDs. In in vitro studies, the interaction of HP-β-CD with a uremic toxin, indole molecule, was much higher than that for the other CDs, as evidenced by Proton nuclear magnetic resonance ((1) H NMR) measurements. These results suggest that the ingestion of HP-β-CD might result in a significant reduction in the levels of pro-oxidants in the gastrointestinal tract, such as uremic toxins, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation. © 2015 Royal Pharmaceutical Society.
    06/2015; DOI:10.1111/jphp.12446
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    ABSTRACT: The inclusion mode of Limaprost in the presence of α- and β-cyclodextrins (CDs) was investigated to gain insight into the stabilization mechanism of Limaprost-alfadex upon the addition of β-CD in the solid state. The inclusion sites of α- and β-CDs were studied by NMR spectroscopic and kinetic methods. With the addition of α- and β-CDs, displacements in (13)C chemical shifts of prostaglandin F2α (PGF2α) were observed in the ω-chain and the five-membered ring, respectively, of the drug. Similar shift changes were observed with the addition of both α- and β-CDs. In two-dimensional (2D) (1)H-NMR spectra, intermolecular correlation peaks were observed between protons of PGF2α and protons of both α- and β-CDs, suggesting that PGF2α interacts with α- and β-CDs to form a ternary complex by including the ω-chain with the former CD and the five-membered ring with the latter. In kinetic studies in aqueous solution, Limaprost was degraded to 17S,20-dimethyl-trans-Δ(2)-PGA1 (11-deoxy-Δ(10)) and 17S,20-dimethyl-trans-Δ(2)-8-iso-PGE1 (8-iso). The addition of α-CD promoted the dehydration to 11-deoxy-Δ(10), while β-CD promoted the isomerization to 8-iso, under these conditions. In the presence of both α- and β-CDs, dehydration and isomerization were also accelerated, supporting the formation of the ternary Limaprost/α-CD/β-CD complex.
    Chemical & pharmaceutical bulletin 05/2015; 63(5):318-25. DOI:10.1248/cpb.c14-00733 · 1.16 Impact Factor
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    ABSTRACT: An intermolecular complex formed from a 1:1 weight ratio of Chitosan (CS, molecular weight 30 kDa) and sulfobutyl ether β-cyclodextrin (SBE-β-CyD, degree of substitution 7) was less soluble than either of the original components. The release of famotidine from tablets composed of a simple mixture of CS and SBE-β-CyD is slower in media at pH 1.2 than at 6.8. Macroscopic observation of tablets and a kinetic analysis of release profiles suggested that, at pH 1.2, the drug was slowly released from the less-soluble CS/SBE-β-CyD complex formed on the surface of the tablet immediately after exposure to water, accompanied by the dissolution of the interpolymer complex and, ultimately, the erosion and disintegration of the tablet. In the case of the medium at pH 6.8, the formation of a gel by CS was the cause of the slow release, especially for CS/SBE-β-CyD tablets which were significantly gelated and both the diameter and thickness of the tablet had expanded. The in vitro slow releasing characteristic of the CS/SBE-β-CyD tablet was reflected in the in vivo absorption of the drug after oral administration to rats. These results suggest that a simple mixing of CA and SBE-β-CyD is potentially useful for the controlled release of a drug. Copyright © 2015. Published by Elsevier B.V.
    International Journal of Pharmaceutics 04/2015; 487(1-2). DOI:10.1016/j.ijpharm.2015.04.022 · 3.65 Impact Factor
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    ABSTRACT: Stable hydrophilic C60(OH)10 nanoparticles were prepared from 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and applied to the treatment of an acetaminophen overdose induced liver Injury. C60(OH)10 nanoparticles were produced by cogrinding α-CD, β-CD, γ-CD and HP-β-CD and characterized in terms of solubility, mean particle diameter, ζ-potential and long term dispersibility in water. Hydrophilic C60(OH)10 nanoparticles with particle sizes less than 50 nm were effectively produced by cogrinding HP-β-CD with C60(OH)10 at a molar ratio of 1:3 (C60(OH)10:CD). The resulting C60(OH)10/HP-β-CD nanoparticles were stable in water and showed no aggregation over a 1 month period. The C60(OH)10/CDs nanoparticles scavenged not only free radicals (DPPH and ABTS radicals) but also reactive oxygen species (O2•− and •OH). When C60(OH)10/HP-β-CD nanoparticles were intraperitoneally administered to mice with a liver injury induced by an overdose of acetaminophen (APAP), the ALT and AST levels were markedly reduced to almost the same level as that for normal mice. Furthermore, the administration of the nanoparticles prolonged the survival rate of liver injured mice, while all of the mice that were treated with APAP died within 40 h. To reveal the mechanism responsible for liver protection by C60(OH)10 nanoparticles, GSH level, CYP2E1 expression and peroxynitrite formation in the liver were assessed. C60(OH)10/HP-β-CD nanoparticles had no effect on CYP2E1 expression and GSH depletion, but suppressed the generation of peroxynitrite in the liver. The findings indicate that the protective effect of C60(OH)10/HP-β-CD nanoparticles was due to the suppression of oxidative stress in mitochondria, as the result of scavenging ROS such as O2•−, NO and peroxynitrite, which act as critical mediators in the liver injuries.
    Biomaterials 03/2015; 45. DOI:10.1016/j.biomaterials.2014.12.032 · 8.56 Impact Factor
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    ABSTRACT: We prepared a gel starting from deacetylated chitin nanofibers by utilizing electrostatic interactions with an anionic cyclodextrin, sulfobutyl ether β-cyclodextrin (SBE-β-CyD). Among the various CyDs tested and their derivatives, SBE-β-CyD formed a stiff, nonfluid elastic gel that can be easily formed into a variety of shapes, whereas other gels prepared from neutral CyDs formed a weak, rather fluid gel. The viscosity of the deacetylated chitin nanofiber/SBE-β-CyD gel was higher by about one order of magnitude at a 1.0 w/v % concentration of SBE-β-CyD. Both the elastic (G′) and viscous (G′′) moduli of the deacetylated chitin-nanofiber gel increased in the presence of SBE-β-CyD, and the G′ values were much higher than the G′′ values. The SBE-β-CyD functioned to reinforce the deacetylated chitin nanofiber gel, by anchoring the fibers into a three-dimensional network through electrostatic interactions.
    Chemistry Letters 03/2015; 44(3):285-287. DOI:10.1246/cl.141004 · 1.23 Impact Factor
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    ABSTRACT: In recent world-wide studies, chitosans were tested as a dietary supplement for inhibiting the absorption of certain lipids and bile acids. We previously demonstrated the antioxidative and renoprotective potential of chitosan supplementation in chronic renal failure using 5/6 nephrectomized rats. In this study, we report the effects of chitosan on oxidative stress and related factors in hemodialysis patients. The ingestion of chitosan over a 12-week period resulted in a significant decrease in serum indoxyl sulfate and phosphate levels, compared with the levels prior to the start of the study. The ingestion of chitosan also resulted in a lowered ratio of oxidized to reduced albumin and a decrease in the level of advanced oxidized protein products. In in vitro studies, chitosan solutions were found to bind 38.5% of the indoxyl sulfate and 17.8% of the phosphate, respectively. Further, the oxidized albumin ratio was correlated with serum indoxyl sulfate levels in vivo. These results suggest that the ingestion of chitosan results in a significant reduction in the levels of pro-oxidants, which include uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation. In addition, the long-term ingestion of chitosan has the potential for use in treating hyperphosphatemia in hemodialysis patients.
    Carbohydrate Polymers 11/2014; 112:152–157. DOI:10.1016/j.carbpol.2014.05.078 · 4.07 Impact Factor
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    ABSTRACT: Recently, a large number of peptides and proteins have been utilized as active pharmaceutical ingredients in the clinical field. However, the stability of peptide and protein drugs is often low. In addition, some peptides and proteins adsorb onto glass or polypropylene tube. In the present study, to improve these pharmaceutical properties of peptides and proteins, we newly prepared glucuronylglucosyl-beta-cyclodextrin (GUG-beta-CyD) conjugate with insulin, a model protein drug, and evaluated its enzymatic or thermal stability and adsorption onto glass or polypropylene tube. The insulin conjugate with GUG-beta-CyD was successfully prepared by condensation of amine group of insulin and carboxyl group of GUG-beta-CyD. Circular dichroism spectra showed that the secondary structure of insulin in this conjugate was retained. Adsorption of insulin onto glass or polypropylene tube was decreased by the conjugation with GUG-beta-CyD. Moreover, enzymatic and thermal stabilities of the conjugate were higher than those of insulin and the mixture of insulin and GUG-beta-CyD. These results suggest that insulin conjugation with GUG-beta-CyD could improve the pharmaceutical properties of insulin.
    Journal of inclusion phenomena and macrocyclic chemistry 10/2014; 80(1-2):107-112. DOI:10.1007/s10847-014-0407-5 · 1.43 Impact Factor
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    ABSTRACT: Despite recent advances in the formulation of orally disintegrating tablets (ODTs), the efforts to enhance the swallowing of the drug after disintegration have been limited. In this study, the feasibility of the combined use of cyclodextrins (CyDs) and a functional drug carrier, hydroxypropylmethylcellulose stearoxy ether (Sangelose®) was investigated to improve usability of ODTs. Glimepiride, a potent third generation hypoglycemic agent for type 2 diabetes was used as a model drug, because it is poorly water-soluble and elimination half life is fairly short. The direct compression method was employed for the preparation of glimepiride tablets, containing CyDs and Sangelose®, and various characteristics of the tablets were examined. In the cases of α-CyD and β-CyD, a short disintegration time with an appropriate hardness was obtained, complying with ODT criteria. On the other hand, γ-CyD, HP-β-CyD and HB-β-CyD increased in the hardness and disintegration time of the tablets. The rheological evaluation revealed that CyDs, except γ-CyD, significantly reduced the viscosity of the fluids after disintegration of the tablets, suggesting an ease of swallowing. This was ascribable to the complexation of the hydrophobic stearoyl moiety of Sangelose® with CyDs after dissolution, leading to the inhibition of the polymer–polymer interaction of Sangelose® and to the decrease in viscosity of the solution. The interaction of glimepiride with α- and β-CyDs was studied by the solubility method, demonstrating that glimepiride formed water-soluble complexes with these CyDs. Results obtained here suggested that α-CyD and β-CyD can be particularly useful for the Sangelose®-based ODT formulation, compared to γ-CyD, HP-β-CyD and HB-β-CyD, because of the short disintegration time of the tablets containing α-CyD and β-CyD, their shear-thinning effect on Sangelose® solutions and their solubility enhancing effect on the drug.
    Journal of inclusion phenomena and macrocyclic chemistry 10/2014; 80(1-2). DOI:10.1007/s10847-014-0386-6 · 1.43 Impact Factor
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    ABSTRACT: The preparation of water-soluble chitosans such as polyethylene glycol (PEG)-grafted derivatives is essential for improving the biocompatibility and water solubility of these types of polysaccharides. In this study, chitosans (CS1; 22kDa, CS2; 38kDa, CS3; 52kDa) with different molecular weights were modified with a succinyl ester derivative of monomethoxypolyethylene glycol (mPEG-COONSu; 2kDa), and the properties of the resulting conjugates (mPEG-CS1, mPEG-CS2, mPEG-CS3) were investigated. The antioxidant properties of these mPEG-CSs were examined using 1) N-centered radicals derived from 1,1'-diphenyl-2-picrylhydrazyl (DPPH), 2) reducing power, based on their ability to reduce Cu(2+) and 3) hydroxyl radicals via the use of ESR spectrometry. The order of their effectiveness was mPEG-CS1> mPEG-CS2> mPEG-CS3, i.e. mPEG-CS1 with a low particle size had the highest scavenging activity of the mPEG-CSs tested. In an in vivo study, we examined the effect of mPEG-CS1 on liver injury, caused by injecting mice with Concanavalin A (Con A). The livers of mice that were treated with mPEG-CS1 were protected from Con A-induced injury. Further, pre-treatment with mPEG-CS1 dramatically reduced the mortality associated with Con A-induced mortality. These findings suggest that mPEG-CS1 could be potentially useful in the treatment of immune-mediated liver injury.
    International Journal of Biological Macromolecules 06/2014; 70. DOI:10.1016/j.ijbiomac.2014.06.026 · 2.86 Impact Factor
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    ABSTRACT: Stabilization against humidity of Limaprost (a Prostaglandin E1 derivative), which is currently marketed as Opalmon(®), was undertaken using b-cyclodextrin (β-CD). Aqueous solutions of Limaprost alfadex/dextran 40 were lyophilized with and without β-CD. Limaprost alfadex lyophilized with β-CD was more chemically stable in humid conditions than that without β-CD. Moreover, the addition of β-CD as an excipient to tablets of these lyophilized composites remarkably improved the stability of Limaprost, and Limaprost in this moisture-resistant formulation was chemically stable for 19 weeks at 30\deg;C, 75% relative humidity. Chemical analysis of Limaprost and its degradation products indicated that degradation proceeded in the inclusion form (i.e., within the CD cavity). Solid (2)H-NMR spectroscopic studies showed that β-CD constrained the molecular mobility of water in the solid state. These results suggested that the stabilization of Limaprost by β-CD was at least partly due to the restricted molecular mobility of water, which acted as a catalytic species for the degradation, and also to the protection of the five-membered ring of Limaprost from water catalytic dehydration through inclusion complex formation with β-CD.
    CHEMICAL & PHARMACEUTICAL BULLETIN 05/2014; 62(8). DOI:10.1248/cpb.c14-00150 · 1.16 Impact Factor
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    ABSTRACT: The photosensitizing ability of C60/2-hydroxypropyl-β- cyclodextrin (HP-β-CyD) nanoparticles under visible light irradiation was studied by electron spin resonance (ESR) and phototoxicity on cancer cells. In addition, the photoinduced antitumor effect to the tumor-bearing mice was evaluated. C60 nanoparticles were prepared by grinding a mixture of HP-β-CyD. The resulting C60/HP-β-CyD nanoparticles were highly-sensitive to visible light and generated higher levels of 1O2 than protoporphyrin IX (PpIX). C60/HP- β-CyD reduced the viability of cancer cells (HeLa cells and A549 cells) in response to irradiation by visible light in a dose-dependent manner. The IC 50 values of the C60/HP-β-CyD nanoparticles was 10 M for HeLa cells and 60 M for A549 cells at an irradiation level of 35 mW/cm 2. The photodynamic effect of C60/HP-β-CyD nanoparticles on the in vivo growth of mouse sarcoma S-180 cells was evaluated after intratumor injection. The outcome of PDT by C60/HP-β-CyD was directly dependent on the dose of irradiated light. Treatment with C 60/HP-β-CyD nanoparticles at a C60 dose of 2.0 mg/kg under visible light irradiation at 350 mW/cm2 (63 J/cm2) markedly suppressed tumor growth, whereas that at 30 J/cm2 was less effective. These findings suggest that C60/HP-β-CyD nanoparticles represent a promising candidate for use in cancer treatment by PDT.
    International Journal of Photoenergy 01/2014; 2014(10):1-8. DOI:10.1155/2014/570506 · 1.56 Impact Factor
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    ABSTRACT: Poor oral absorption of a factor Xa inhibitor, DX-9065, is partly due to the interaction with bile acids in the gastrointestinal tract. The aim of this study is to improve the oral bioavailability of DX-9065 by cyclodextrins (CyDs) capable of interfering with such interaction. The abilities of the CyDs to interfere with the interaction between DX-9065 and sodium chenodeoxycholate were evaluated using equilibrium dialysis. The interaction between DX-9065 and the CyDs was studied spectroscopically. Effects of the CyDs on the oral absorption of DX-9065 were examined in rats. Hydroxypropyl-β-CyD and γ-CyD were effective in interfering with the interaction between DX-9065 and sodium chenodeoxycholate as a representative bile acid. Spectroscopic studies revealed that DX-9065 was included into the CyD cavity to form inclusion complexes in an acidic medium. With dissociation of the carboxyl group of DX-9065 in a neutral medium, the stability of the complexes was decreased to such an extent that DX-9065 in the cavity is replaced with co-existing bile acids. The average area under the plasma concentration-time curve value after oral administration of DX-9065 with hydroxypropyl-β-CyD was 2.5 times higher than that of DX-9065 alone with a statistical difference in rats. We suggest that the CyDs are useful in designing oral formulations of DX-9065 with an improved bioavailability.
    11/2013; 65(11):1598-1606. DOI:10.1111/jphp.12137
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    ABSTRACT: The stability of solutions of fullerene C60 with human serum albumin (C60/HSA) has not been studied in detail. In this study, we report on the preparation of stable C60/HSA solutions that are formed via the formation of C60/HP-β-CyD nanoparticles, i.e. by transferring C60 molecules from HP-β-CyD to HSA molecules, and an investigation of the reactive oxygen species on the behavior of the resulting C60/HSA. Structural and functional properties were examined by spectroscopic techniques, including circular dichroism (CD), fluorescent spectra (FI), the electron spin resonance spin-trapping method, and by the cell viability test using A549 cells. Aqueous C60/HSA solutions with a small distribution size, excellent dispersion stability and a high dispersion concentration were obtained without the use of organic solvents. CD and FI spectra indicated that the HSA had undergone structural changes as the result of C60/HSA formation. Binding experiments indicated that C60/HSA had increased Site I and Site II-ligand binding capabilities. The HSA, in the form of C60/HSA was, therefore, conformationally altered, and its binding capabilities were enhanced. Radical scavenging studies using the 1,1'-diphenyl-2-picrylhydrazyl radical showed that C60/HSA had an increased antioxidant activity, compared to HSA alone. Further, C60/HSA efficiently generated not only superoxide anion radicals O2(·-) but also singlet oxygen (1)O2 through photoirradiation. C60/HSA showed cell toxicity characteristics after light irradiation, but no toxicity was observed in the absence of irradiation. C60/HSA has not only an excellent stability and antioxidant activity, but also has substantial phototoxicity properties. It thus appears that HSA can be used as a carrier of C60 in drug delivery systems for photodynamic therapy.
    Life sciences 07/2013; 93(7). DOI:10.1016/j.lfs.2013.06.021 · 2.70 Impact Factor
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    ABSTRACT: A new polymorph of acetohexamide (Form VI) was prepared via the formation of a complex with 2-hydoxybutyl-β-cyclodextrin (HB-β-CD) in aqueous solution. An alkaline solution of acetohexamide and HB-β-CD was adjusted to pH 4.0 by titration with hydrochloric acid. The resulting opaque solution was filtered through paper and allowed to stand at 4°C for 24hours. The resulting precipitate was isolated on a filter and analyzed for polymorph content by powder X-ray diffractometry and thermal analysis. The diffraction pattern and thermal behavior of the precipitate was different from those of previously reported acetohexamide polymorphs (Forms I, III, IV and V), indicating that a new polymorph of the drug, i.e. Form VI was produced. This new polymorph was fairly stable against conversion to a stable form even at accelerated storage conditions. Crystalline Form VI was highly soluble in water and dissolved more rapidly than the other known polymorphs. This property was reflected in the blood concentrations of the drug after oral administration to rats.
    International Journal of Pharmaceutics 06/2013; 453(2). DOI:10.1016/j.ijpharm.2013.06.026 · 3.65 Impact Factor
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    ABSTRACT: The objective of this study is to evaluate the ability of C(60)/2-hydroxypropyl-β-cyclodextrin (HP-β-CyD) naonparticles to generate reactive oxygen species (ROS) and to induce cell toxicity by the photoirradiation. C(60) nanoparticles were prepared by cogrinding with HP-β-CyD for 3 h at 4°C under reduced pressure. The photodynamic activity of C(60)/HP-β-CyD nanoparticles was evaluated by spectroscopic methods, including the electron spin resonance spin-trapping method, and by the cell viability test using Hela cells. C(60)/HP-β-CyD nanoparticles efficiently generated not only superoxide anion radical (O(2)(·-)) and hydroxyl radical (·OH), but also singlet oxygen ((1)O(2)) through photoirradiation. The ROS generation was enhanced by decreasing the mean particle diameter of C(60) nanoparticles, and the particle size smaller than 90 nm showed a high generation of ·OH and (1)O(2). In addition, HP-β-CyD enhanced the generation of (1)O(2), compared with polyvinylpyrrolidone (an effective solubillizer for C(60)), due to partial disposition of C(60) in the hydrophobic CyD cavity. Furthermore, C(60) /HP-β-CyD nanoparticles showed cell toxicity after the light irradiation, but no toxicity was observed without the light irradiation. Therefore, HP-β-CyD is useful for the preparation of stable C(60) nanoparticles with high ROS generation ability, and C(60)/HP-β-CyD nanoparticles are a promising photosensitizer for photodynamic therapy.
    Journal of Pharmaceutical Sciences 09/2012; 101(9):3390-7. DOI:10.1002/jps.23045 · 2.59 Impact Factor
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    ABSTRACT: The effect of chitosan on oxidative stress and chronic renal failure was investigated using 5/6 nephrectomized rats. The ingestion of chitosan over a 4-week period resulted in a significant decrease in total body weight, glucose, serum creatinine and indoxyl sulfate levels (P = 0.0011, P = 0.0006, P = 0.0012, and P = 0.0005, respectively), compared with the non-treated nephrectomized group. The ingestion of chitosan also resulted in a lowered ratio of oxidized to reduced albumin (P = 0.003) and an increase in biological antioxidant potential (P = 0.023). Interestingly, the oxidized albumin ratio was correlated with serum indoxyl sulfate levels in vivo. These results suggest that the ingestion of chitosan results in a significant reduction in the levels of pro-oxidants, such as uremic toxins, in the gastrointestinal tract, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.
    Carbohydrate Polymers 06/2012; 89(1):302–304. DOI:10.1016/j.carbpol.2012.03.014 · 4.07 Impact Factor
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    ABSTRACT: We previously reported that glucuronylglucosyl-β-cyclodextrin (GUG-β-CyD) conjugate with polyamidoamine starburst dendrimer (GUG-β-CDE conjugate) with the average degree of substitution (DS) of cyclodextrin (CyD) of 1.8 (GUG-β-CDE conjugate (DS 1.8)), showed remarkably higher gene transfer activity than α-CyD/dendrimer conjugate (α-CDE conjugate (DS 1.2)) and β-CyD/dendrimer conjugate (β-CDE conjugate (DS 1.3)) in vitro and in vivo. In this study, to clarify the enhancing mechanism for high gene transfer activity of GUG-β-CDE conjugate (DS 1.8), we investigated the physicochemical properties, cellular uptake, endosomal escape and nuclear translocation of the plasmid DNA (pDNA) complexes as well as pDNA release from the complexes. The particle size, ζ-potential and cellular uptake of GUG-β-CDE conjugate (DS 1.8)/pDNA complex were mostly comparable to those of α-CDE conjugate (DS 1.2) and β-CDE conjugate (DS 1.3). Meanwhile, GUG-β-CDE conjugate (DS 1.8)/pDNA complex was likely to have high endosomal escaping ability and nuclear localization ability in A549 and RAW264.7 cells. In addition, the pDNA condensation and decondensation abilities of GUG-β-CDE conjugate (DS 1.8) were lower and higher than that of α-CDE conjugate (DS 1.2) or β-CDE conjugate (DS 1.3), respectively. These results suggest that high gene transfer activity of GUG-β-CDE conjugate (DS 1.8) could be, at least in part, attributed to high endosomal escaping ability, nuclear localization ability and suitable pDNA release from its complex.
    International Journal of Pharmaceutics 04/2012; 426(1-2):239-47. DOI:10.1016/j.ijpharm.2012.01.039 · 3.65 Impact Factor

Publication Stats

11k Citations
598.68 Total Impact Points


  • 2006-2015
    • Sojo University
      Kumamoto, Kumamoto, Japan
  • 1977-2011
    • Kumamoto University
      • • Department of Clinical Pharmaceutical Sciences
      • • Graduate School of Pharmaceutical Sciences
      • • Department of Physical Pharmaceutics
      Kumamoto, Kumamoto Prefecture, Japan
  • 1987
    • Tokushima Bunri University
      • Faculty of Pharmaceutical Sciences
      Tokushima-shi, Tokushima-ken, Japan
  • 1981-1983
    • Miyazaki Medical Association Hospital
      Миядзаки, Miyazaki, Japan
  • 1976
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 1974-1976
    • Nagoya City University
      • Faculty of Pharmaceutical Sciences
      Nagoya, Aichi, Japan