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1.
Metallomics ; 11(10): 1648-1656, 2019 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-31528927

RESUMO

The organo-osmium half-sandwich complex [(η6-p-cymene)Os(Ph-azopyridine-NMe2)I]+ (FY26) exhibits potent antiproliferative activity towards cancer cells and is active in vivo. The complex is relatively inert, but rapidly activated in cells by displacement of coordinated iodide. Here, we study time-dependent accumulation of FY26 in A2780 human ovarian cancer cells at various temperatures in comparison with the chlorido metabolite [(η6-p-cymene)Os(Ph-azopyridine-NMe2)Cl]+ (FY25). Mathematical models described the time evolution of FY26 and FY25 intracellular and extracellular concentrations taking into account both cellular transport (influx and efflux) and the intracellular conversion of FY26 to FY25. Uptake of iodide complex FY26 at 37 °C was 17× faster than that of chloride complex FY25, and efflux 1.4× faster. Osmium accumulation decreased markedly after 24 h of exposure. Modelling revealed that this phenomenon could be explained by complex-induced reduction of osmium uptake, rather than by a model involving enhanced osmium efflux. The intracellular osmium concentration threshold above which reduction in drug uptake was triggered was estimated as 20.8 µM (95% confidence interval [16.5, 30]). These studies provide important new insight into the dynamics of transport of this organometallic anticancer drug candidate.


Assuntos
Antineoplásicos/farmacocinética , Complexos de Coordenação/farmacocinética , Osmio/farmacocinética , Neoplasias Ovarianas/tratamento farmacológico , Pró-Fármacos/farmacocinética , Linhagem Celular Tumoral , Feminino , Humanos , Cinética , Compostos Organometálicos/farmacocinética , Neoplasias Ovarianas/metabolismo
2.
J Inorg Biochem ; 185: 26-29, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29730234

RESUMO

Microfocus synchrotron x-ray fluorescence (SXRF) imaging focussed on detection of the Os LIII edge shows that the organo­osmium metallodrug candidate [(ŋ6-p-cym)Os(Azpy-NMe2)I]+ (p-cym = p-cymene, Azpy-NMe2 = 2-(p-([dimethylamino]phenylazo)pyridine)) [1] penetrates efficiently into the interior of A2780 human ovarian cancer cell spheroids, a model for a solid tumour. The accompanying changes in Zn and Ca distribution suggest that the complex causes nuclear damage and initiates signalling events for cell death, consistent with findings for cultured cancer cell monolayers. Such tumour penetration is likely to be important for combatting resistance to chemotherapy, which is becoming a problem for current clinical platinum drugs.


Assuntos
Antineoplásicos/farmacocinética , Compostos Organometálicos/farmacocinética , Osmio/farmacocinética , Espectrometria por Raios X/métodos , Antineoplásicos/química , Cálcio/metabolismo , Linhagem Celular Tumoral , Feminino , Humanos , Compostos Organometálicos/química , Osmio/química , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Esferoides Celulares/metabolismo , Síncrotrons , Zinco/metabolismo
3.
Metallomics ; 10(3): 388-396, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29513313

RESUMO

Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used to study the spatial distribution of two metallodrugs with anticancer activities in vivo, namely the organoruthenium plecstatin-1 (1) and its isosteric osmium analogue (2), in liver, kidneys, muscles and tumours of treated mice bearing a CT-26 tumour after single-dose i.p. administration. To the best of our knowledge, this is the first time that the spatial distribution of an osmium drug candidate has been investigated using LA-ICP-MS in tissues. Independent measurements of the average ruthenium and osmium concentration via microwave digestion and ICP-MS in organs and tumours were in good agreement with the LA-ICP-MS results. Matrix-matched standards (MMS) ranging from 1 to 30 µg g-1 were prepared to quantify the spatial distributions of the metals and the average metal content of the MMS samples was additionally quantified by ICP-MS after microwave digestion. The recoveries for osmium and ruthenium in the MMS were 105% and 101% on average, respectively, validating the sample preparation procedure of the MMS. Preparation of MMS was carried out under an argon atmosphere to prevent oxidation of osmium-species to the volatile OsO4. The highest metal concentrations were found in the liver, followed by kidney, lung and tumour tissues, while muscles displayed only very low quantities of the respective metal. Both metallodrugs accumulated in the cortex of the kidneys more strongly compared to the medulla. Interestingly, osmium from 2 was largely located at the periphery and tissue edges, whereas ruthenium from 1 was observed to penetrate deeper into the organs and tumours.


Assuntos
Antineoplásicos/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Terapia a Laser , Espectrometria de Massas/métodos , Imagem Molecular/métodos , Osmio/administração & dosagem , Rutênio/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/farmacocinética , Osmio/farmacocinética , Rutênio/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas
4.
Analyst ; 142(13): 2327-2332, 2017 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-28585637

RESUMO

An orally active osmium anticancer compound was reliably quantified in the organs of treated mice by inductively coupled plasma-mass spectrometry (ICP-MS) by adding a stabilizing solution consisting of ascorbic acid, thiourea and EDTA during sample preparation and avoiding oxidizing conditions. The limits of detection (LOD) and quantification (LOQ) of 189Os were determined in liver tissue to be 0.02 and 0.075 µg kg-1, respectively. In spiked liver tissue, the internal precision showed a relative standard deviation (RSD) of 4%, a matrix recovery of 92% and a digestion recovery of 99%. A similar quantification protocol was developed for cellular accumulation studies in vitro. The cells were lysed with a non-oxidizing lysis buffer consisting of 150 mmol L-1 NaCl, 1.0% Triton X-100, 0.1% SDS, and 50 mmol L-1 Tris at pH 8.0 before adding the stabilizing solution. The osmium compound was compared with an isosteric ruthenium analogue and they displayed similar cellular accumulation and organ distribution profiles.


Assuntos
Antineoplásicos/análise , Espectrometria de Massas , Osmio/análise , Animais , Antineoplásicos/farmacocinética , Técnicas de Cultura de Células , Limite de Detecção , Camundongos , Osmio/farmacocinética , Rutênio
5.
J Nucl Med ; 31(4): 523-5, 1990 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-2109051

RESUMO

The influence of four pH adjustment agents on the biologic behavior of osmium-191 (191Os) impurity in 191Os/191mIr generator eluates was studied. Extended body clearance and biodistribution studies were performed in mice. The solutions to be injected were obtained by eluting generators with a 0.9% NaCl solution at pH 1. The pH of these eluates was adjusted to 5-9 with succinate, phosphate, lysine or NaOH solution. Our results demonstrate that the biologic behavior of these generator eluates is significantly dependent on the agent used for pH adjustment. Buffering with lysine leads to the best results: (a) the mice show no adverse reaction after injection of 150 human doses and the body clearance is very rapid and (b) more than 75% I.D. at 24 hr postinjection. Preliminary calculations based on these results suggest a significant decrease in the estimated patient radiation dose when lysine buffered 191Os/191mIr generator eluates are used for radionuclide angiography.


Assuntos
Isótopos , Osmio , Radioisótopos , Geradores de Radionuclídeos , Animais , Soluções Tampão , Concentração de Íons de Hidrogênio , Irídio , Lisina/farmacologia , Camundongos , Camundongos Endogâmicos ICR , Osmio/farmacocinética , Fosfatos/farmacologia , Hidróxido de Sódio/farmacologia , Succinatos/farmacologia , Ácido Succínico , Distribuição Tecidual
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