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1.
Small ; 18(16): e2106570, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35263020

RESUMO

Manganese ferrite nanoparticles display interesting features in bioimaging and catalytic therapies. They have been recently used in theranostics as contrast agents in magnetic resonance imaging (MRI), and as catalase-mimicking nanozymes for hypoxia alleviation. These promising applications encourage the development of novel synthetic procedures to enhance the bioimaging and catalytic properties of these nanomaterials simultaneously. Herein, a cost-efficient synthetic microwave method is developed to manufacture ultrasmall manganese ferrite nanoparticles as advanced multimodal contrast agents in MRI and positron emission tomography (PET), and improved nanozymes. Such a synthetic method allows doping ferrites with Mn in a wide stoichiometric range (Mnx Fe3-x O4 , 0.1 ≤ x ≤ 2.4), affording a library of nanoparticles with different magnetic relaxivities and catalytic properties. These tuned magnetic properties give rise to either positive or dual-mode MRI contrast agents. On the other hand, higher levels of Mn doping enhance the catalytic efficiency of the resulting nanozymes. Finally, through their intracellular catalase-mimicking activity, these ultrasmall manganese ferrite nanoparticles induce an unprecedented tumor growth inhibition in a breast cancer murine model. All of these results show the robust characteristics of these nanoparticles for nanobiotechnological applications.


Assuntos
Meios de Contraste , Nanopartículas , Animais , Catalase , Compostos Férricos , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês , Camundongos
2.
Biomed Chromatogr ; 29(8): 1249-58, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25616154

RESUMO

IKH12 is a novel histone deacetylase 6 selective inhibitor. A rapid and sensitive liquid chromatography tandem mass spectrometry method was developed and validated for the quantification of IKH12 in rat plasma and tissue with kendine 91 as internal standard (IS). The samples were prepared by liquid-liquid extraction with tert-butyl methyl ether. The chromatographic separation was accomplished by using a Zorbax Extend C18 4.6 × 150 mm, 5 µm column, with a mobile phase consisting of methanol and 0.1% formic acid (75:25 v/v). Multiple reaction monitoring, using electrospray ionization in positive ion mode, was employed to quantitatively detect IKH12 and IS. The monitored transitions were set at m/z 418 → 252 and 444 → 169 for IKH12 and kendine 91, respectively. The calibration curve was linear over the concentration range 2-1000 ng mL(-1) . The intra- and inter-assay precision and accuracy of the quality controls and the limit of quantification were satisfactory in all cases (according to European Medicines Agency guidelines). Stability studies showed that plasma samples were stable in the chromatography rack for 24 h and at -80°C for 2 months and also after three freeze-thaw cycles. This method was successfully applied to a pharmacokinetic study of IKH12 in rat.


Assuntos
Antineoplásicos/sangue , Inibidores de Histona Desacetilases/sangue , Ácidos Hidroxâmicos/sangue , Prolina/análogos & derivados , Espectrometria de Massas por Ionização por Electrospray/métodos , Animais , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção , Extração Líquido-Líquido/métodos , Masculino , Éteres Metílicos/química , Prolina/sangue , Ratos Wistar , Espectrometria de Massas em Tandem/métodos
4.
J Med Chem ; 64(17): 12855-12864, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34460263

RESUMO

An undecamer oligonucleotide probe based on a pair of deoxythymidines flanked by several modified nucleotides is a specific and highly efficient biosensor for micrococcal nuclease (MNase), an endonuclease produced by Staphylococcus aureus. Herein, the interaction mode and cleavage process on such oligonucleotide probes are identified and described for the first time. Also, we designed truncated pentamer probes as the minimum-length substrates required for specific and efficient biosensing. By means of computational (virtual docking) and experimental (ultra-performance liquid chromatography-mass spectrometry and matrix-assisted laser desorption ionization time-of-flight) techniques, we perform a sequence/structure-activity relationship analysis, propose a catalytically active substrate-enzyme complex, and elucidate a novel two-step phosphodiester bond hydrolysis mechanism, identifying the cleavage sites and detecting and quantifying the resulting probe fragments. Our results unravel a picture of both the enzyme-biosensor complex and a two-step cleavage/biosensing mechanism, key to the rational oligonucleotide design process.


Assuntos
Proteínas de Bactérias/química , Desoxirribonucleases/metabolismo , Desenho de Fármacos , Oligonucleotídeos/química , Staphylococcus aureus/metabolismo , Técnicas Biossensoriais , Cromatografia Líquida , Desoxirribonucleases/genética , Espectrometria de Massas , Modelos Moleculares , Simulação de Acoplamento Molecular , Conformação de Ácido Nucleico , Conformação Proteica , Especificidade por Substrato
5.
Artigo em Inglês | MEDLINE | ID: mdl-18583203

RESUMO

A liquid chromatography-tandem mass spectrometric method (LC-MS/MS) has been developed and validated to determine the concentration of Kendine 91 in mice plasma and tissues. Simvastatin was employed as the internal standard. Separation was performed on a C8 column, with a mobile phase consisting of methanol and aqueous 10 mM formic acid (73:27 v/v). Both analyte and internal standard were determined using electrospray ionization and the MS data acquisition was via multiple-reaction monitoring (MRM) in positive scanning mode. Quantification was performed using the transitions m/z 444-->169 and 441-->325 for Kendine 91 and simvastatin, respectively. The method was validated with respect to linearity, accuracy, precision, recovery and stability. This assay has been successfully applied to a pharmacokinetic study after intravenous injection of Kendine 91 in mice in a dose of 10mg/kg.


Assuntos
Cromatografia Líquida/métodos , Inibidores Enzimáticos/análise , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Espectrometria de Massas em Tandem/métodos , Animais , Calibragem , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Camundongos , Sensibilidade e Especificidade
6.
Cancer Chemother Pharmacol ; 64(1): 153-9, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19002463

RESUMO

PURPOSE: The present investigation was undertaken to characterize the pharmacokinetics and oral bioavailability of Kendine 91 in mice and to compare it with other HDAC (histone deacetylases) inhibitors. METHODS: After administration of a single intravenous dose (10 mg/kg) or a single oral dose (50 mg/kg) blood and tissues samples were collected and analysed by HPLC/MS/MS. RESULTS: Elimination half-life was higher than that of SAHA (5.87 vs. 0.38 h after intravenous (IV) administration and 10.29 versus 0.75 h after oral administration). Absolute oral bioavailability was found to be 18%. Total body clearance (7.72 l/h/kg) was greater than the hepatic blood flow of 5.4 l/h/kg in mice and larger than glomerular filtration rate in mice (0.84 l/h/kg). Tissue levels and distribution volume indicate a high capacity of Kendine 91 to distribute into tissues. CONCLUSIONS: This preliminary pharmacokinetic evaluation prompts us to believe that it is worth pursuing further development of Kendine 91 as an anticancer drug.


Assuntos
Antineoplásicos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/farmacocinética , Pirróis/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Feminino , Taxa de Filtração Glomerular , Meia-Vida , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Espectrometria de Massas em Tandem , Distribuição Tecidual , Vorinostat
7.
J Org Chem ; 72(12): 4313-22, 2007 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-17506578

RESUMO

The stereochemical outcomes observed in the thermal and microwave-assisted [3 + 2] cycloaddition between stabilized azomethine ylides and nitrostyrenes have been analyzed using experimental and computational approaches. It has been observed that, in the absence of solvent, three stereoisomers are formed, both under classical heating conditions and under microwave irradiation. This result contrasts with that observed in solution under classical thermal conditions. The 4-nitropyrrolidines obtained in this way can be aromatized under further microwave irradiation to yield mixtures of pyrroles and 4-nitropyrroles. It is found that ground state cycloadditions between imines and nitrostyrenes take place by three-step mechanisms. The first step involves enolization of the starting imine, and this is followed by a pseudopericyclic 10-electron [1.4]-hydrogen shift. Finally, the cycloaddition takes place by a relatively asynchronous aromatic six-electron supra-supra thermal mechanism.

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