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1.
Biochemistry ; 48(20): 4273-84, 2009 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-19331399

RESUMO

Studies in animals have reported that normalized or elevated Cu levels can inhibit or even remove Alzheimer's disease-related pathological plaques and exert a desirable amyloid-modifying effect. We tested engineered nanocarriers composed of diverse core-shell architectures to modulate Cu levels under physiological conditions through bypassing the cellular Cu uptake systems. Two different nanocarrier systems were able to transport Cu across the plasma membrane of yeast or higher eukaryotic cells, CS-NPs (core-shell nanoparticles) and CMS-NPs (core-multishell nanoparticles). Intracellular Cu levels could be increased up to 3-fold above normal with a sublethal dose of carriers. Both types of carriers released their bound guest molecules into the cytosolic compartment where they were accessible for the Cu-dependent enzyme SOD1. In particular, CS-NPs reduced Abeta levels and targeted intracellular organelles more efficiently than CMS-NPs. Fluorescently labeled CMS-NPs unraveled a cellular uptake mechanism, which depended on clathrin-mediated endocytosis in an energy-dependent manner. In contrast, the transport of CS-NPs was most likely driven by a concentration gradient. Overall, nanocarriers depending on the nature of the surrounding shell functioned by mediating import of Cu across cellular membranes, increased levels of bioavailable Cu, and affected Abeta turnover. Our studies illustrate that Cu-charged nanocarriers can achieve a reasonable metal ion specificity and represent an alternative to metal-complexing agents. The results demonstrate that carrier strategies have potential for the treatment of metal ion deficiency disorders.


Assuntos
Peptídeos beta-Amiloides/química , Cobre/metabolismo , Peptídeos/química , Peptídeos beta-Amiloides/metabolismo , Animais , Transporte Biológico , Células CHO , Cobre/química , Cricetinae , Cricetulus , Portadores de Fármacos , Endocitose , Corantes Fluorescentes/farmacologia , Humanos , Nanopartículas/química , Nanotecnologia/métodos , Polímeros/química
2.
Bioorg Med Chem Lett ; 19(3): 1030-4, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19097889

RESUMO

In this paper new dendritic core-shell architectures with pH-labile linkers based on hyperbranched polyglycerol cores and biocompatible poly(ethylene glycol) shells were synthesized which encapsulate the anticancer agent doxorubicin and a dye for near-infrared imaging, an indotricarbocyanine. Acid-sensitive properties of the new nanocarriers and in vitro cytotoxicity of the doxorubicin-nanocarrier are presented as well as preliminary data regarding their toxicity and tumor targeting potential in nude mice.


Assuntos
Antineoplásicos/síntese química , Carbocianinas/química , Células Dendríticas/metabolismo , Doxorrubicina/química , Portadores de Fármacos , Nanotecnologia/métodos , Animais , Antineoplásicos/farmacologia , Materiais Biocompatíveis/química , Carbocianinas/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Glicerol/química , Concentração de Íons de Hidrogênio , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Nanopartículas/química , Polímeros/química
3.
Macromol Biosci ; 7(8): 968-74, 2007 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-17665413

RESUMO

A simple general synthetic concept to build dendritic core-shell architectures with pH-labile linkers based on hyperbranched PEI cores and biocompatible PEG shells is presented. Using these dendritic core-shell architectures as nanocarriers, the encapsulation and transport of polar dyes of different sizes is studied. The results show that the acid-labile nanocarriers exhibit much higher transport capacities for dyes than unfunctionalized hyperbranched PEI. The cleavage of imine bonds and controlled release of the polar dyes revealed that weak acidic condition (pH approximately 5.0) could cleave the imine bonds linker and release the dyes up to five times faster than neutral conditions (pH = 7.4).


Assuntos
Corantes/química , Dendrímeros/química , Portadores de Fármacos/química , Nanopartículas/química , Polietilenoimina/química , Água/química , Benzaldeídos/síntese química , Benzaldeídos/química , Vermelho Congo/química , Concentração de Íons de Hidrogênio , Polietilenoglicóis/química , Rosa Bengala/química , Solubilidade , Relação Estrutura-Atividade , Timolftaleína/análogos & derivados , Timolftaleína/química , Fatores de Tempo
4.
J Drug Target ; 14(6): 367-74, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17092837

RESUMO

In this paper a simple general synthetic concept was used to generate dendritic core-shell architectures based on hyperbranched poly(ethylene imine) cores and different shells which contain aliphatic chains and poly(ethylene glycol) chains, respectively. Using these dendritic core-shell architectures as nanocarriers we studied the encapsulation and transport of polar drugs, such as congo red. The results showed that the acid labile nanocarriers exhibited much higher transport capacities for congo red than the bare poly(ethylene imine). This gives an opportunity for the controlled release of encapsulated dyes and drugs by a pH-triggered cleavage of the imine bond. In two cases the pH-sensitivity was studied and a relatively high stability of the imine bond was observed at pH 8, while fast cleavage occurred at pH 5-7. This pH difference correspond to the pH-shift in malignant tissues (tumor, infection) compared to normal tissue, which could trigger the release of the encapsulated drugs.


Assuntos
Dendrímeros/química , Portadores de Fármacos/química , Nanoestruturas/química , Aldeídos/química , Soluções Tampão , Clorofórmio , Corantes/química , Composição de Medicamentos/métodos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Iminas/síntese química , Iminas/química , Modelos Químicos , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Polietilenoglicóis/síntese química , Polietilenoglicóis/química , Polietilenos/síntese química , Polietilenos/química , Solubilidade , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta , Tecnologia Farmacêutica/métodos , Tolueno
5.
Photochem Photobiol ; 80: 112-4, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15339225

RESUMO

We report on the emission spectra and emission quantum yields of a newly synthesized hypocrellin dye, 2-demethoxy-2,3-ethylenediamino hypocrellin B (EDAHB), and its parent HB in different solvents of varying polarity. Our results demonstrate that EDAHB is one of the few dyes that exhibit highly solvent polarity-dependent fluorescence in the useful region (680-730 nm). Therefore, it offers some applications in the biomedical field as a fluorescent probe molecule. The solvatochromic effect of EDAHB is proposed to be due to a distinct change in the dipole moment of the dye on excitation. A photoinduced intramolecular proton transfer and a photoinduced intramolecular electron transfer process are considered relevant for the fluorescence properties of HB and EDAHB, respectively.


Assuntos
Perileno/análogos & derivados , Perileno/química , Fármacos Fotossensibilizantes/química , Quinonas/química , Quinoxalinas/química , Elétrons , Prótons , Espectrometria de Fluorescência/métodos
6.
Photochem Photobiol ; 78(4): 411-5, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14626671

RESUMO

To improve the amphiphilicities and red absorption of the hypocrellins, three novel 2-amino-2-demethoxy-hypocrellins were synthesized by the mild reactions of hypocrellin B with 4-(2-amino-ethyl)morpholine, N,N-dimethylethylenediamine and 1-(2-amino-ethyl)piperazine, respectively. The structures of these derivatives were characterized with proton nuclear magnetic resonance, infrared and mass spectra (MS). The ultraviolet-visible absorption and fluorescence spectra of the derivatives were measured and the new amino-substituted hypocrellins showed strong absorption in the domain of the phototherapeutic window (600-900 nm). Their amphiphilicities evaluated via the partition coefficients between n-octanol and phosphate-buffered saline buffer improved remarkably. Electron paramagnetic resonance spin-trapping measurements were used to investigate the photodynamic action of the three compounds in the presence of oxygen. Singlet oxygen (1O2) and superoxide anion radical (O2.-) generated by illuminating the hypocrellin derivatives in aerobic solution were observed.


Assuntos
Perileno/análogos & derivados , Perileno/síntese química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Quinonas/síntese química , Perileno/química , Fenol , Fármacos Fotossensibilizantes/química , Quinonas/química , Espécies Reativas de Oxigênio , Espectrometria de Fluorescência
7.
J Photochem Photobiol B ; 72(1-3): 61-7, 2003 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-14644567

RESUMO

Two phenmethylamino hypocrellin B derivatives are novel photodynamic agents synthesized by a mild reaction between hypocrellin B and phenmethylamine. The red absorption of the photosensitizers is enlarged distinctly and the peri-hydroxylated perylenequinone structure of the parent HB is preserved. 9,10-diphenyl-anthracene (DPA) bleaching and electron paramagnetic resonance (EPR) spin trapping techniques were used to study the photodynamic activities of the phenmethylamino hypocrellin B derivatives in the presence of oxygen. Singlet oxygen (1O2) and superoxide anion radical (O2*-) generated in the process of illumination of the phenmethylamino hypocrellin B in aerobic solution were observed. The photodamage of PMAHBs to MGC803 cancer cells was investigated in vitro. The results in vitro reveal that the phenmethylamino hypocrellin B derivatives show a much less significant decrease in cytotoxicity than that of their parent HB. It exhibits higher selectivity of light-orientation, which can decrease the damage to normal tissues by irradiating the tumor tissues, and so increases the drug safety.


Assuntos
Perileno/análogos & derivados , Perileno/síntese química , Perileno/farmacologia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/farmacologia , Quinonas/síntese química , Quinonas/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Sobrevivência Celular/efeitos da radiação , Relação Dose-Resposta a Droga , Humanos , Estimulação Luminosa/métodos , Fotoquimioterapia/métodos
8.
J Photochem Photobiol B ; 67(1): 64-70, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-12007469

RESUMO

TiO2 semiconductor colloids have been successfully employed in environmental clean-up, antibacterial and bactericidal action under ultraviolet light due to its strong redox ability and high yield of active oxygen species (1O2, O2*-), *OOH) generation. Hypocrellin B, isolated from Hypocrella bambusae (B.et.Br) Sacc, a natural pigment with strong and broad absorption over the visible light region, was used in our work in an attempt to extend the photoresponse of TiO2 to visible light and maintain the high generation of active oxygen under visible light illumination. The formation of the HB-TiO2 chelate was characterized by UV-Vis and surface enhanced raman spectroscopy (SERS) and it was found that the chelate still had high efficiency of active oxygen generation. The possible generation mechanism was explored by Electron Paramagnetic Resonance (EPR) and time-resolved transient spectra techniques, showing that singlet oxygen (1O2) and superoxide radical anion (O2*-)) were produced via energy transfer and electron transfer, respectively. The application of HB-TiO2 chelate in environment protection and bacteria sterilization was implied.


Assuntos
Perileno/análogos & derivados , Perileno/química , Fármacos Fotossensibilizantes/química , Quinonas/química , Oxigênio Singlete/química , Superóxidos/química , Titânio/química , Quelantes , Coloides , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Estrutura Molecular , Transtornos de Fotossensibilidade
9.
J Photochem Photobiol B ; 68(2-3): 73-8, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12468200

RESUMO

Hypocrellin B (HB) is a natural pigment with a promising application in the photodynamic therapy (PDT) for anticancer treatment. The photobleaching of HB in non-polar organic solvents and in liposomes in aqueous solution were investigated by the measurements of absorption spectra, quenching experiments and determination of photoproducts. Control experiments indicated that the sensitizer, oxygen and light were all essential for the photobleaching of HB, which suggested that it was mainly self-sensitized photooxidation. The illumination of HB with visible light in aerobic non-polar solvent generated singlet oxygen efficiently [Phi(1O(2))=0.76] which then attacked the sensitizer HB with formation of an endoperoxide product. The endoperoxide of HB was unstable at room temperature and underwent predominantly loss of singlet oxygen with regeneration of parent HB. The singlet oxygen released from the endoperoxide of HB was detected with chemical trapping experiments. When HB was embedded in EPC liposomes, no endoperoxide product and no singlet oxygen release from the photobleaching process of HB were detected. The quenching experiments indicated that the singlet oxygen mechanism (type II) played an important role in the non-polar solvent and the free radical mechanism (type I) was predominant in liposomal aqueous solution for the photobleaching of HB.


Assuntos
Lipossomos , Perileno , Perileno/análogos & derivados , Fármacos Fotossensibilizantes , Quinonas , Estrutura Molecular , Perileno/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Quinonas/química , Solventes , Espectrofotometria Ultravioleta
10.
Chemistry ; 14(11): 3311-5, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18286555

RESUMO

Mesoporous pure silicas and functionalized silica with a narrow pore size distribution centered at 3.8 nm were prepared by a novel template, amphiphilic dendritic polyglycerol. The resulting silica materials were characterized by electron microscopy; nitrogen adsorption; (1)H, (13)C, and (29)Si solid-state cross-polarization magic-angle spinning NMR spectroscopy. It was shown that the template could be completely removed from the pure and functionalized silica in an environmentally friendly way by means of a simple water extraction procedure. Furthermore, it was shown that these materials could be easily functionalized, for example, by employing aminopropyl groups. Thus, a new environmentally friendly pathway to this fascinating class of silica material has been opened.


Assuntos
Dióxido de Silício/síntese química , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão
11.
Chemistry ; 12(22): 5779-84, 2006 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-16718731

RESUMO

The kinetics of the reaction of several alcohols (benzyl alcohol, ethanol, 1-phenylethanol, cyclohexanol, and 1-methyl-1-phenylethanol) with a selection of anhydrides (acetic anyhydride, propionic anhydride, isobutyric anhydride, isovaleric anhydride, and pivalic anhydride) as catalyzed by 4-(N,N-dimethylamino)pyridine (DMAP)/triethyl amine have been studied in CH(2)Cl(2) at 20 degrees C. In all cases the reaction kinetics can be described by rate laws containing a DMAP-catalyzed term and an uncatalyzed (background) term. The rate constants for the background reaction respond sensitively to changes in the steric demand of the alcohol and the anhydride substrates, making the reaction of cyclohexanol with acetic anhydride 526 times faster than the reaction with pivalic anhydride. Steric effects are even larger for the catalyzed reaction and the reactivity difference between acetic and pivalic anhydride exceeds a factor of 8000 for the reaction of cyclohexanol. There is, however, no linear correlation between the steric effects on the catalyzed and the uncatalyzed part. As a consequence there are substrate combinations with dominating catalytic terms (such as the reaction of benzyl alcohol with isobutyric anhydride), while other substrate combinations (such as the reaction of cyclohexanol with pivalic anhydride) are characterized through a dominating background process. The implications of these findings for the kinetic resolution of alcohols are discussed.

12.
Chemistry ; 11(16): 4751-7, 2005 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-15924289

RESUMO

The acetylation of tert-butanol with acetic anhydride catalyzed by 4-(dimethylamino)pyridine (DMAP) has been studied at the Becke3 LYP/6-311 + G(d,p)//Becke3 LYP/6-31G(d) level of theory. Solvent effects have been estimated through single-point calculations with the PCM/UAHF solvation model. The energetically most favorable pathway proceeds through nucleophilic attack of DMAP at the anhydride carbonyl group and subsequent formation of the corresponding acetylpyridinium/acetate ion pair. Reaction of this ion pair with the alcohol substrate yields the final product, tert-butylacetate. The competing base-catalyzed reaction pathway can either proceed in a concerted or in a stepwise manner. In both cases the reaction barrier far exceeds that of the nucleophilic catalysis mechanism. The reaction mechanism has also been studied experimentally in dichloromethane through analysis of the reaction kinetics for the acetylation of cyclohexanol with acetic anhydride, in the presence of DMAP as catalyst and triethylamine as the auxiliary base. The reaction is found to be first-order with respect to acetic anhydride, cyclohexanol, and DMAP, and zero-order with respect to triethyl amine. Both the theoretical as well as the experimental studies strongly support the nucleophilic catalysis pathway.

13.
Bioorg Med Chem Lett ; 14(6): 1499-501, 2004 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-15006390

RESUMO

A novel diamino-substituted hypocrellin derived from hypocrellin B (HB) was synthesized by a mild method. The red absorption of the resulting product was significantly enhanced relative to the parent hypocrellins and any other hypocrellin derivatives, and the active oxygen species generating abilities were enhanced distinctly, which will remarkably improve its photodynamic therapy effectiveness.


Assuntos
Ressonância Magnética Nuclear Biomolecular/métodos , Perileno/análogos & derivados , Perileno/química , Fármacos Fotossensibilizantes/química , Quinonas/química , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Éter de Diematoporfirina/análise , Éter de Diematoporfirina/química , Espectroscopia de Ressonância de Spin Eletrônica , Perileno/análise , Fenol , Quinonas/análise
14.
J Org Chem ; 68(5): 2048-50, 2003 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-12608836

RESUMO

Methylated hypocrellins were obtained and characterized by satisfactory 1HNMR, UV-vis, IR, and mass data, and their absorption and fluorescence emission spectra were studied. A previous report of methylated hypocrellin (J. Phys. Chem. A 1999, 103, 7949) appears to be in error.


Assuntos
Perileno/análogos & derivados , Perileno/síntese química , Quinonas/síntese química , Espectrometria de Massas , Metano/análogos & derivados , Metano/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fenol , Espectrofotometria Infravermelho , Espectrofotometria Ultravioleta
15.
Photochem Photobiol Sci ; 2(8): 871-6, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-14521225

RESUMO

Cyclohexylamino-substituted hypocrellin B (CHAHB) has been synthesized with the aim of improving the red absorption and specific affinity for malignant tumors over those of the parent compound. Irradiation of a deoxygenated DMSO solution of CHAHB generates a strong electron paramagnetic resonance (EPR) signal, which is assigned to the semiquinone radical anion of CHAHB with the aid of a series of experimental results. In the presence of oxygen, superoxide radical anions (O2*-) are generated via electron transfer from CHAHB*-, the precursor, to ground-state molecular oxygen. Hydroxyl radicals were detected by spin-trapping EPR when an oxygen-saturated aqueous solution containing CHAHB and DMPO was irradiated. Singlet oxygen (1O2) is produced via energy transfer from triplet CHAHB to ground-state oxygen molecules, with a sharply decreased quantum yield, i.e. 0.11. Furthermore, cell survival studies reveal CHAHB exhibits much higher photodynamic activities than its parent hypocrellins. The strongly enhanced photodynamic activities and sharply decreased quantum yield of 1O2 generation suggest that the type I (free radical) mechanism may play a significant role in CHAHB-PDT, rather than the type II (singlet oxygen) mechanism found in photofrin-PDT.


Assuntos
Benzoquinonas/química , Perileno/análogos & derivados , Perileno/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Quinonas/química , Espécies Reativas de Oxigênio/química , Ânions , Sobrevivência Celular/efeitos da radiação , Espectroscopia de Ressonância de Spin Eletrônica , Transporte de Elétrons , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Fotodegradação , Células Tumorais Cultivadas
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