Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
1.
Biochim Biophys Acta Mol Cell Res ; 1864(6): 1018-1027, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28109792

RESUMO

Glioblastoma is the most common malignant brain tumor. The heterogeneity at the cellular level, metabolic specificities and plasticity of the cancer cells are a challenge for glioblastoma treatment. Identification of cancer cells endowed with stem properties and able to propagate the tumor in animal xenografts has opened a new paradigm in cancer therapy. Thus, to increase efficacy and avoid tumor recurrence, therapies need to target not only the differentiated cells of the tumor mass, but also the cancer stem-like cells. These therapies need to be effective on cells present in the hypoxic, slightly acidic microenvironment found within tumors. Such a microenvironment is known to favor more aggressive undifferentiated phenotypes and a slow-growing "quiescent state" that preserves the cells from chemotherapeutic agents, which mostly target proliferating cells. Based on these considerations, we performed a differential screening of the Prestwick Chemical Library of approved drugs on both proliferating and quiescent glioblastoma stem-like cells and identified bisacodyl as a cytotoxic agent with selectivity for quiescent glioblastoma stem-like cells. In the present study we further characterize bisacodyl activity and show its efficacy in vitro on clonal macro-tumorospheres, as well as in vivo in glioblastoma mouse models. Our work further suggests that bisacodyl acts through inhibition of Ca2+ release from the InsP3 receptors.


Assuntos
Bisacodil/farmacologia , Neoplasias Encefálicas/patologia , Sinalização do Cálcio , Glioblastoma/patologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Células-Tronco Neoplásicas/patologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Humanos , Células-Tronco Neoplásicas/metabolismo
2.
J Control Release ; 246: 60-70, 2017 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-27956144

RESUMO

Efficiency of polyethylenimine (PEI) for nucleic acid delivery is affected by the size of the carrier and length of the nucleic acids. For instance, PEIs with molecular weights between 10-30kDa provide optimal DNA delivery activity whereas PEIs with molecular weights below 1.8kDa are ineffective. The activity of PEI is also severely diminished by substitution of DNA for shorter nucleic acids such as mRNA or siRNA. Here, through chemical modification of the primary amines to aromatic domains we achieved nucleic acid delivery by the 1.8kDa polyethylenimine (PEI) particles. This modification did not affect the PEI buffering abilities but enhanced its pH-sensitive aggregation, enabling stabilization of the polyplex outside the cell while still allowing nucleic acid release following cellular entry. The aromatic PEIs were then evaluated for their gene, mRNA, siRNA and 2'O-methyl phosphorothioate oligonucleotide in vitro transfection abilities. The salicylamide-grafted PEI showed to be a reliable carrier for delivering nucleic acids with cytoplasmic activity such as the mRNA and siRNA or nuclear diffusible oligonucleotide. It was then further equipped with polyethyleneglycol (PEG) and the delivery efficiency of the copolymer was tested in vivo for regeneration of dystrophin in the muscle of mdx mouse through a 2'O-methyl phosphorothioate-mediated splicing modulation. Intramuscular administration of polyplexes resulted in dystrophin-positive fibers in a mouse model of Duchenne muscular dystrophy without apparent toxicity. These findings indicate that precise modifications of low molecular weight PEI improve its bio-responsiveness and yield delivery vehicles for nucleic acids of various types in vitro and in vivo.


Assuntos
DNA/administração & dosagem , Técnicas de Transferência de Genes , Oligonucleotídeos Fosforotioatos/administração & dosagem , Plasmídeos/administração & dosagem , Polietilenoimina/química , RNA Mensageiro/administração & dosagem , RNA Interferente Pequeno/administração & dosagem , Animais , DNA/genética , Éxons , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos mdx , Oligonucleotídeos Fosforotioatos/genética , Plasmídeos/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética
3.
ACS Appl Mater Interfaces ; 8(45): 30665-30670, 2016 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-27804286

RESUMO

A novel generation of pH-responsive photopolymerized diacetylenic amphiphile (PDA) micelles with a diameter of 10 nm was designed and optimized for the intracellular delivery of siRNAs. Dialysis and photopolymerization of the micelles allowed a strong reduction of the cytotoxicity of the nanovector, while the hydrophilic histidine headgroup permitted enhancing the siRNA delivery potential by improving the endosomal escape via imidazole protonation. These PDA-micellar systems were fully characterized by DLS, TEM, and DOSY-NMR experiments. The resulting bioactive complexes of PDA-micelles with siRNA were shown to have an optimal size below 100 nm.


Assuntos
Micelas , Sistemas de Liberação de Medicamentos , Endossomos , Histidina , Concentração de Íons de Hidrogênio , Polímeros , RNA Interferente Pequeno
4.
J Inorg Biochem ; 99(12): 2423-35, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16271395

RESUMO

The interactions of three bis(amide) ligands derived from tartaric acid with copper (II) were investigated in aqueous solution by a combination of potentiometry, UV-vis spectrophotometry, electron paramagnetic resonance (EPR), and mass spectrometry. The formation constants of the complexes were measured and their relative structures were reported. The sites of complexation of these ligands are investigated based mostly on their electronic and EPR spectra and on the comparison with the behaviour of some analog compounds.

5.
J Med Chem ; 57(7): 2908-19, 2014 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-24625069

RESUMO

Apelin is the endogenous ligand for the previously orphaned G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart, and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial. In this context, E339-3D6 (1) was described as the first nonpeptidic apelin receptor agonist. We show here that 1 is actually a mixture of polymethylated species, and we describe an alternative and versatile solid-phase approach that allows access to highly pure 27, the major component of 1. This approach was also applied to prepare a series of derivatives in order to identify the crucial structural determinants required for the ligand to maintain its affinity for the apelin receptor as well as its capacity to promote apelin receptor signaling and internalization. The study of the structure-activity relationships led to the identification of ligands 19, 21, and 38, which display an increased affinity compared to that of 27. The latter and 19 behave as full agonists with regard to cAMP production and apelin receptor internalization, whereas 21 is a biased agonist toward cAMP production. Interestingly, the three ligands display a much higher stability in mouse plasma (T1/2 > 10 h) than the endogenous apelin-17 peptide 2 (T1/2 < 4 min).


Assuntos
Dipeptídeos/química , Dipeptídeos/farmacologia , Descoberta de Drogas , Fluoresceínas/química , Fluoresceínas/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Animais , Receptores de Apelina , Células CHO , Cricetulus , AMP Cíclico/metabolismo , Ligantes , Camundongos , Estrutura Molecular , Plasma/química , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
6.
Acta Biomater ; 9(2): 4985-93, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23000009

RESUMO

We report here the synthesis of a diblock linear polymer of oligo(benzylethylenimine)-b-polyethylenimine (OBzEI-PEI) and investigate its gene delivery properties. The linear copolymer OBzEI-PEI was prepared in a straightforward manner by acidic hydrolysis of a diblock polyoxazoline, which had been made by sequential polymerization of 4-benzyl-2-ethyl-2-oxazoline followed by 2-ethyl-2-oxazoline. pH titration and DNA complexation profiles of the new polymer are similar to regular linear PEIs, but with higher gene transfection efficiencies in various cell lines despite a decreased cellular uptake of plasmid DNA. Further experiments suggest that the OBzEI tail complements the intrinsic proton-sponge endosomolytic activities of PEI with an acid pH-sensitive membrane-perturbing activity.


Assuntos
Aziridinas/química , Membrana Celular/metabolismo , Técnicas de Transferência de Genes , Polietilenoimina/análogos & derivados , Polietilenoimina/química , Animais , Linhagem Celular , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , DNA/metabolismo , Eletroforese em Gel de Ágar , Hemólise/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Tamanho da Partícula , Polietilenoimina/síntese química , Polietilenoimina/farmacologia , Potenciometria , Ovinos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA