RESUMO
To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of â¼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.
Assuntos
Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Paclitaxel/química , Paclitaxel/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Vitamina E/análogos & derivados , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Química Farmacêutica/métodos , Portadores de Fármacos/química , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Meia-Vida , Humanos , Camundongos , Micelas , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Oxirredução , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley , Vitamina E/químicaRESUMO
Au and Ag biochips were fabricated to investigate the influence of pH upon the chemiluminescence (CL) of luminol at vicinity of surface-adsorbed peroxidase. A nanoscaled-corrugation of the metal induces an enhancement of the luminol CL which is maximal in the pH range favoring peroxidase catalysis and greater for gold than for silver. This is the proof that, in the CL process, the reactions involving peroxidase are surface-enhanced near corrugated surfaces.
Assuntos
Ouro/química , Luminol/química , Luminol/metabolismo , Membranas Artificiais , Nanopartículas Metálicas/química , Peroxidase/metabolismo , Prata/química , Adsorção , Biocatálise , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio , Luminescência , Nanotecnologia , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
Multi-cycle chemotherapy is commonly used in the clinic, while the phenomena of enrichment of cancer stem cells (CSCs) and enhanced multi-drug resistance (MDR) are commonly involved. This research was designed for evaluating this successive administration. Chitosan oligosaccharide-g-stearic acid (CSOSA) polymer was used as the drug delivery system (DDS) to perform tri-cycle chemotherapy on a new tumor model induced by mammosphere cells. In vitro, on CSCs enriched mammospheres model, the doxorubicin-loaded CSOSA (CSOSA/DOX) displayed an improved growth inhibition effect measured by acid phosphatase assay (APH). While in vivo, the CSOSA/DOX micelles blocked tumor progression and led to a marked decrease of CSCs proportion as well as MDR capacity. What's more, the CSOSA/DOX helped decay the microenvironment and attenuate systemic side effects. We concluded that the CSOSA polymer could be a potential DDS for long-term multi-cycle chemotherapy in antitumor research.