Kaneto Uekama

Sojo University, Kumamoto, Kumamoto, Japan

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Publications (389)935.69 Total impact

  • [Show abstract] [Hide abstract]
    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 · 8.31 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 · 3.92 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 · 3.10 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; DOI:10.1248/cpb.c14-00150 · 1.38 Impact Factor
  • International Journal of Photoenergy 01/2014; 2014:1-8. DOI:10.1155/2014/570506 · 2.66 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; DOI:10.1016/j.lfs.2013.06.021 · 2.30 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 · 3.79 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 · 3.01 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 · 3.92 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 · 3.79 Impact Factor
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    ABSTRACT: The present work refers to a method to selectively modify the crystal habit of acetylsalicylic acid (ASA) through the use of the cyclic oligosaccharide derivatives 2-hydroxybutyl-β-cyclodextrin (HB-β-CD) and 2,6-di-O-methyl-β-cyclodextrin (DM-β-CD) as a growth inhibitor. ASA crystallized in plate crystals in solutions containing only drug. On the other hand, the addition of HB-β-CD or DM-β-CD markedly changed the crystal habit of the drug to needle crystals that elongated along the crystallographic b-axis. The habit modification of these CDs was attributable to the suppression of the crystal growth of ASA toward the c-axis direction, which is perpendicular to the {001} surface and consisted of phenyl and methyl groups of ASA. These results suggested that HB- and DM-β-CDs inhibited the access of ASA to the {001} face due to the inclusion complex formation with the drug and/or due to the adsorption of the amphiphilic hosts on this face. These CDs can work as a tailor-made additive and may be useful for control of crystal habits of drugs.
    Crystal Growth & Design 03/2012; 12(4):1985–1991. DOI:10.1021/cg201691c · 4.56 Impact Factor
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    ABSTRACT: We previously reported that polyamidoamine STARBURST dendrimer (generation 3, G3) (dendrimer) conjugate with α-cyclodextrin (α-CyD) having an average degree of substitution of 2.4 of α-CyD (α-CDE) provided remarkable aspects as novel carriers for DNA and small-interfering RNA. To develop novel α-CDE derivatives with tumor cell specificity, we prepared folate-appended α-CDEs (Fol-α-CDEs) and folate-polyethylene glycol (PEG)-appended α-CDEs (Fol-PαCs) with the various degrees of substitution of folate (DSF), and evaluated in vitro and in vivo gene transfer activity, cytotoxicity, cellular association and physicochemical properties. In vitro gene transfer activity of Fol-α-CDEs (G3, DSF 2, 5 or 7) was lower than that of α-CDE (G3) in KB cells, folate receptor (FR)-overexpressing cancer cells. Of the three Fol-PαCs (G3, DSF 2, 5 or 7), Fol-PαC (G3, DSF 5) had the highest gene transfer activity in KB cells. The activity of Fol-PαC (G3, DSF 5) was significantly higher than that of α-CDE (G3) in KB cells, but not in A549 cells, FR-negative cells. Negligible cytotoxicity of the plasmid DNA (pDNA) complex with Fol-PαC (G3, DSF 5) was observed in KB cells or A549 cells up to a charge ratio of 100/1 (carrier/pDNA). The cellular association of the pDNA complex with Fol-PαC (G3, DSF 5) could be mediated by FR on KB cells, resulting in its efficient cellular uptake. Fol-PαC (G3, DSF 5) had a higher binding affinity with folate-binding protein than α-CDE (G3), although the physicochemical properties of pDNA complex with Fol-PαC (G3, DSF 5) were almost comparable to that with α-CDE (G3), although the onset charge ratio and the compaction ability of Fol-PαC (G3, DSF 5) were slightly different. Fol-PαC (G3, DSF 5) tended to show a higher gene transfer activity than α-CDE (G3) 12 h after intratumoral administration in mice. These results suggest that Fol-PαC (G3, DSF 5), not Fol-α-CDEs, could be potentially used as a FR-overexpressing cancer cell-selective DNA carrier.
    Cancer gene therapy 03/2012; 19(5):358-66. DOI:10.1038/cgt.2012.9 · 2.55 Impact Factor
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    ABSTRACT: Long-acting insulin products are desired that provide sustained blood glucose lowering without blood glucose level peaks. In the present study, to obtain the more desirable blood glucose lowering effect of long-acting insulin products, we investigated the effect of maltosyl-β-cyclodextrin (G(2)-β-CyD) on physicochemical properties and pharmacokinetics/pharmacodynamics of insulin glargine, which is the one of the most widely used insulin analog. G(2)-β-CyD increased the solubility and suppressed the aggregation of insulin glargine in phosphate buffer at 9.5, probably due to the interaction of G(2)-β-CyD with aromatic residues of the insulin glargine such as tyrosine. In addition, the dissolution rates of insulin glargine from its precipitates were increased by a complexation with G(2)-β-CyD. Subcutaneous administration of an insulin glargine solution with G(2)-β-CyD to rats gradually decreased blood glucose levels and provided a sustained blood glucose lowering effect without showing the glucose level peaks. These results suggest that G(2)-β-CyD can be a useful excipient for sustained release and a truly peak-less formulation of insulin glargine.
    International Journal of Pharmaceutics 01/2012; 422(1-2):33-9. DOI:10.1016/j.ijpharm.2011.10.022 · 3.79 Impact Factor
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    ABSTRACT: The objective of this study is to evaluate the ability of C60/2‐hydroxypropyl‐β‐cyclodextrin (HP‐β‐CyD) naonparticles to generate reactive oxygen species (ROS) and to induce cell toxicity by the photoirradiation. C60 nanoparticles were prepared by cogrinding with HP‐β‐CyD for 3 h at 4°C under reduced pressure. The photodynamic activity of C60/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. C60/HP‐β‐CyD nanoparticles efficiently generated not only superoxide anion radical (O2·−) and hydroxyl radical (·OH), but also singlet oxygen (1O2) through photoirradiation. The ROS generation was enhanced by decreasing the mean particle diameter of C60 nanoparticles, and the particle size smaller than 90 nm showed a high generation of ·OH and 1O2. In addition, HP‐β‐CyD enhanced the generation of 1O2, compared with polyvinylpyrrolidone (an effective solubillizer for C60), due to partial disposition of C60 in the hydrophobic CyD cavity. Furthermore, C60/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 C60 nanoparticles with high ROS generation ability, and C60/HP‐β‐CyD nanoparticles are a promising photosensitizer for photodynamic therapy. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:3390–3397, 2012
    Journal of Pharmaceutical Sciences 01/2012; 101(9). · 3.01 Impact Factor
  • Kaneto Uekama
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    ABSTRACT: The α-, β-, and γ-CyDs are the most common natural CyDs, consisting of six, seven, and eight glucose units, respectively. Among the natural CyDs, bioadaptable γ-cyclodextrin (γ-CyD) is useful to improve the undesired properties of drug molecules through the formation of inclusion complex. Recently, various kinds of CyD derivatives such as hydrophilic, hydrophobic, amphiphatic and anionic CyDs have been developed, anticipating the design of CyD-based drug delivery system. The objective of this contribution is to outline our recent findings on the combinational use of γ-CyD and functional ingredients, focusing on the ability to increase the drug absorption, the ability to control the rate and time profiles of drug release, and the ability to deliver a drug to a targeted site. In addition, the multi-functional characteristic of hydroxyalkylated CyDs, in particular, 2-hydroxypropyl-β-CyD (HP-β-CyD) is applicable to design the novel pharmaceutical formulation, focusing on the ability to form hydrophilic nano-particles. Moreover, some amphiphatic CyDs such as 2,6-di-O-methyl-β-CyD (DM-β-CyD) and 2-hydroxybutyl-β-CyD (HB-β-CyD) are useful to control the crystallization and polymorphic transition of solid drugs and will provide an opportunity to isolate labile intermediate metastable polymorphs. On the basis of above-mentioned knowledge, this review explores the use of CyDs to better understand their pharmaceutical applications as well as their limitations in the approach of CyD-based drug delivery system.
    YAKUGAKU ZASSHI 01/2012; 132(1):85-105. DOI:10.1248/yakushi.132.85 · 0.31 Impact Factor
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    ABSTRACT: In this study, we evaluated the polyamidoamine starburst dendrimer (dendrimer, generation 2: G2) conjugate with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-β-cyclodextrin (GUG-β-CDE (G2)) as a gene transfer carrier. The in vitro gene transfer activity of GUG-β-CDE (G2, degree of substitution (DS) of cyclodextrin (CyD) 1.8) was remarkably higher than that of dendrimer (G2) conjugate with α-CyD (α-CDE (G2, DS 1.2)) and that with β-CyD(β-CDE (G2, DS 1.3)) in A549 and RAW264.7 cells. The particle size, ζ-potential, DNase I-catalyzed degradation, and cellular association of plasmid DNA (pDNA) complex with GUG-β-CDE (G2, DS 1.8) were almost the same as those of the other CDEs. Fluorescent-labeled GUG-β-CDE (G2, DS 1.8) localized in the nucleus 6 h after transfection of its pDNA complex in A549 cells, suggesting that nuclear localization of pDNA complex with GUG-β-CDE (G2, DS 1.8), at least in part, contributes to its high gene transfer activity. GUG-β-CDE (G2, DS 1.8) provided higher gene transfer activity than α-CDE (G2, DS 1.2) and β-CDE (G2, DS 1.3) in kidney with negligible changes in blood chemistry values 12 h after intravenous injection of pDNA complexes with GUG-β-CDE (G2, DS 1.8) in mice. In conclusion, the present findings suggest that GUG-β-CDE (G2, DS 1.8) has the potential for a novel polymeric pDNA carrier in vitro and in vivo.
    Journal of Drug Targeting 12/2011; 20(3):272-80. DOI:10.3109/1061186X.2011.645163 · 2.72 Impact Factor
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    ABSTRACT: Insulin glargine is a synthetic long-acting insulin product used for patients with diabetes mellitus. In this study, to obtain the further desirable blood-glucose lowering profile of insulin glargine, we investigated the effects of β-cyclodextrin sulfate (Sul-β-CyD) and sulfobutylether β-cyclodextrin (SBE7-β-CyD) on physicochemical properties of insulin glargine and pharmacokinetics/pharmacodynamics of insulin glargine after subcutaneous injection to rats. Sul-β-CyD and SBE7-β-CyD increased solubility of insulin glargine. SBE7-β-CyD suppressed the formation of oligomer and enhanced the dissolution rate of insulin glargine from its precipitate, compared to that of Sul-β-CyD. Additionally, we revealed that after subcutaneous administration of an insulin glargine solution, SBE7-β-CyD, but not Sul-β-CyD, increased bioavailability and sustained the blood-glucose lowering effect, possibly due to the inhibitory effects of SBE7-β-CyD on the enzymatic degradation at the injection site. These results suggest that SBE7-β-CyD could be a useful excipient for sustained release of insulin glargine.
    12/2011; 2011:195146. DOI:10.1155/2011/195146

Publication Stats

9k Citations
935.69 Total Impact Points

Institutions

  • 2006–2015
    • Sojo University
      Kumamoto, Kumamoto, Japan
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1977–2011
    • Kumamoto University
      • • Graduate School of Pharmaceutical Sciences
      • • Department of Clinical Pharmaceutical Sciences
      • • Department of Physical Pharmaceutics
      Kumamoto-shi, Kumamoto Prefecture, Japan
  • 2000
    • Kissei Pharmaceuticals Co., Ltd.
      Shonai, Nagano, Japan
  • 1999
    • University of Kansas
      • Department of Pharmaceutical Chemistry
      Lawrence, Kansas, United States
  • 1992
    • University of Baltimore
      Baltimore, Maryland, United States
  • 1987
    • Tokushima Bunri University
      • Faculty of Pharmaceutical Sciences
      Tokushima-shi, Tokushima-ken, Japan