DEFAR - Artigos publicados em periódicos
URI permanente para esta coleçãohttp://www.hml.repositorio.ufop.br/handle/123456789/531
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Item Mechanistic insights into the intracellular release of doxorubicin from pH-sensitive liposomes.(2021) Reis, Samara Bonesso dos; Silva, Juliana de Oliveira; Fossa, Fernanda Garcia; Leite, Elaine Amaral; Souza, Angelo Malachias de; Lana, Gwenaelle Elza Nathalie Pound; Mosqueira, Vanessa Carla Furtado; Oliveira, Mônica Cristina de; Barros, André Luís Branco de; Jesus, Marcelo Bispo depH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a desirable behavior in the treatment of cancer cells. Previously, we have shown that pH-sensitive liposomes accumulate in tumor tissues of mice, in which an acidic environment accelerates drug delivery. Ultimately, these formulations can be internalized by tumor cells and take the endosome-lysosomal route. However, the mechanism of doxorubicin release and intracellular traffic of pH-sensitive liposomes remains unclear. To investigate the molecular mechanisms underlying the intracellular release of doxorubicin from pH-sensitive liposomes, we followed HeLa cells viability, internalization, intracel lular trafficking, and doxorubicin’s intracellular delivery mechanisms from pH-sensitive (SpHL-DOX) and non pH-sensitive (nSpHL-DOX) formulations. We found that SpHL-DOX has faster internalization kinetics and intracellular release of doxorubicin, followed by strong nuclear accumulation compared to nSpHL-DOX. The increased nuclear accumulation led to the activation of cleaved caspase-3, which efficiently induced apoptosis. Remarkably, we found that chloroquine and E64d enhanced the cytotoxicity of SpHL-DOX. This knowledge is paramount to improve the efficiency of pH-sensitive liposomes or to be used as a rational strategy for developing new formulations to be applied in vivo.Item Caspofungin effects on electrocardiogram of mice : an evaluation of cardiac safety.(2021) Paula, Danielle Cristiane Correa de; Leite, Elaine Amaral; Araújo, Carolina Morais; Branquinho, Renata Tupinambá; Guimarães, Homero Nogueira; Guimarães, Andrea GrabeCaspofungin is an echinocandin, exhibiting efcacy against most Candida species invasive infection. Its cardiotoxicity was reported in isolated rat heart and ventricular myocytes, but in vivo and clinical studies are insufcient. Our objective was to evaluate caspofungin in vivo cardiac efects using an efcacious dose against Candida albicans. Female Swiss mice were infected with C. albicans, and treated with caspofungin, 5 or 10 mg/kg, intraperitoneal along 5 days. Survival rate and colony forming units (CFU) into vital organs were determined. For cardiac efects study, mice were treated with caspofungin 10 mg/ kg, and electrocardiogram (ECG) signal was obtained on C. albicans-infected mice, single dose-treated, and uninfected mice treated along 5 days, both groups to measure ECG intervals. Besides, ECG was also obtained by telemetry on uninfected mice to evaluate heart rate variability (HRV) parameters. The MIC for caspofungin on the wild-type C. albicans SC5314 strain was 0.3 μg/ml, indicating the susceptible. Survival rate increased signifcantly in infected mice treated with caspo fungin compared to mice treated with vehicle. None of the survived infected mice presented positive CFU after treatment with 10 mg/kg. C. albicans infection induced prolongation of QRS, QT, and QTc intervals; caspofungin did not alter this efect. Caspofungin induced increase of PR and an additional increase of QRS after 24 h of a single dose in infected mice. No signifcant alterations occurred in ECG intervals and HRV parameters of uninfected mice, after caspofungin treatment. Caspofungin showed in vivo cardiac relative safety maintaining its antifungal efcacy against C. albicans.Item Physical and biological effects of paclitaxel encapsulation on disteraroylphosphatidylethanolamine-polyethyleneglycol polymeric micelles.(2020) Oda, Caroline Mari Ramos; Gasperini, Antonio Augusto Malfatti; Souza, Angelo Malachias de; Lana, Gwenaelle Elza Nathalie Pound; Mosqueira, Vanessa Carla Furtado; Fernandes, Renata Salgado; Oliveira, Mônica Cristina de; Barros, André Luís Branco de; Leite, Elaine AmaralSimple size observations of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2000) polymeric micelles (PM) with different compositions including or not paclitaxel (PTX) are unable to evidence changes on the nanocarrier structure. In such system a detailed characterization using highly sensitive techniques such as X-ray scattering and asymmetric flow field flow fractionation coupled to multi-angle laser light scattering and dynamic light scattering (AF4-MALS-DLS) is mandatory to observe effects that take place by the addition of PTX and/or more lipid-polymer at PM, leading to complex changes on the structure of micelles, as well as in their supramolecular organization. SAXS and AF4-MALS-DLS suggested that PM can be found in the medium separately and highly organized, forming clusters of PM in the latter case. SAXS fitted parameters showed that adding the drug does not change the average PM size since the increase in core radius is compensated by the decrease in shell radius. SAXS observations indicate that PEG conformation takes place, changing from brush to mushroom depending on the PM composition. These findings directly reflect in in vivo studies of blood clearance that showed a longer circulation time of blank PM when compared to PM containing PTX.Item Paclitaxel-loaded pH-sensitive liposome : new insights on structural and physicochemical characterization.(2018) Monteiro, Liziane Oliveira Fonseca; Souza, Angelo Malachias de; Lana, Gwenaelle Elza Nathalie Pound; Paniago, Rogerio Magalhães; Mosqueira, Vanessa Carla Furtado; Oliveira, Mônica Cristina de; Barros, André Luís Branco de; Leite, Elaine AmaralA long-circulating and pH-sensitive liposome containing paclitaxel (SpHL-PTX) was recently developed by our group. Once in an acidic environment, for example, tumors, these liposomes undergo destabilization, releasing the encapsulated drug. In this way, the aim of this study was to evaluate the molecular and supramolecular interactions between the lipid bilayer and PTX in similar biological environment conditions. High-sensitivity analyses of SpHL-PTX structures were obtained by the small-angle X-ray scattering technique combined with other techniques such as dynamic light scattering, asymmetric flow field-flow fractionation, transmission electron microscopy, and high-performance liquid chromatography. The results showed that PTX incorporation in the liposomal bilayer clearly leads to changes in supramolecular organization of dioleoylphosphatidylethanolamine (DOPE) molecules, inducing the formation of more ordered structures. Changes in supramolecular organization were observed at lower pH, indicating that pH sensitivity was preserved even in the presence of fetal bovine serum proteins. Furthermore, morphological and physicochemical characterization of SpHL-PTX evidenced the formation of nanosized dispersion suitable for intravenous administration. In conclusion, a stable nanosized dispersion of PTX was obtained at pH 7.4 with suitable parameters for intravenous administration. At lower pH conditions, the pH sensitivity of the system was clearly evidenced by changes in the supramolecular organization of DOPE molecules, which is crucial for the delivery of PTX into the cytoplasm of the targeted cells. In this way, the results obtained by different techniques confirm the feasibility of SpHL as a promising tool to PTX delivery in acidic environments, such as tumors.Item Toxicological study of a new doxorubicin-loaded pH-sensitive liposome : a preclinical approach.(2018) Silva, Juliana de Oliveira; Miranda, Sued Eustaquio Mendes; Leite, Elaine Amaral; Sabino, Adriano de Paula; Borges, Karina Braga Gomes; Cardoso, Valbert Nascimento; Cassali, Geovanni Dantas; Guimarães, Andrea Grabe; Oliveira, Mônica Cristina de; Barros, André Luís Branco deDoxorubicin (DOX) is widely used in cancer treatment, however, the use of this drug is often limited due to its cardiotoxic side effects. In order to avoid these adverse effects, the encapsulation of DOX into nanosystems has been used in the last decades. In this context, pH-sensitive liposomes have been shown promising for delivering cytotoxic agents into tumor cells, however, the lack of information about in vivo toxicity of this nanocarrier has impaired translational studies. Therefore, the aim of this work was to investigate the acute toxicity and cardiotoxicity of DOX-loading pH-sensitive liposomes (SpHL-DOX). To achieve this, female BALB/c mice, after intravenous administration, were monitored by means of clinical, laboratory, histopathological and electrocardiographic (ECG) analyses. Results indicate that SpHL was able to prevent renal toxicity and the hepatic injury was less extensive than free DOX. In addition, lower body weight loss was associated with less ECG QT interval prolongation to animals receiving SpHL-DOX (14.6 ± 5.2%) compared to animals receiving free DOX (35.7 ± 4.0%) or non-pH-sensitive liposomes (nSpHL-DOX) (47.0 ± 9.8%). These results corroborate with SpHL-DOX biodistribution studies published by our group. In conclusion, the SpHL-DOX showed less toxic effects on mice compared to free DOX or nSpHL-DOX indicating that SpHL-DOX is a promising strategy to reduce the serious cardiotoxic effects of DOX.Item Early signs of cardiac diastolic dysfunction in ovariectomized WKY and SHR female rats.(2018) Martins, Thales de Andrade; Mourad, M.; Bideaux, P.; Guimarães, Andrea Grabe; Mosqueira, Vanessa Carla Furtado; Leite, Elaine Amaral; Leite, Romulo; Sicard, P.; Richard, S.Half of patients with heart failure (HF) have diastolic dysfunction but preserved EF (> 50%; HFpEF). There is no specific treatment. Aging populations, and particularly women, are more widely concerned. Why are women more likely than men to develop HFpEF? Despite possible limitations, small animal models could provide comprehensive approaches to identify/test novel therapeutic targets.Item Polymeric nanostructures for drug delivery : characterization by atomic force microscopy.(2005) Mosqueira, Vanessa Carla Furtado; Leite, Elaine Amaral; Barros, Cristina Maria de; Vilela, José Mário Carneiro; Andrade, Margareth SpanglerItem Poly-caprolactone nanocapsules morphological features by atomic force microscopy.(2005) Leite, Elaine Amaral; Vilela, José Mário Carneiro; Mosqueira, Vanessa Carla Furtado; Andrade, Margareth SpanglerItem Cardiotoxicity reduction induced by halofantrine entrapped in nanocapsule devices.(2007) Leite, Elaine Amaral; Guimarães, Andrea Grabe; Guimarães, Homero Nogueira; Coelho, George Luiz Lins Machado; Barratt, Gillian; Mosqueira, Vanessa Carla FurtadoThe main objective of the present study was to evaluate the reduction in halofantrine (Hf) toxicity, an antimalarial drug frequently associated with QT interval prolongation in electrocardiogram, by its entrapment in poly-ε-caprolactone nanocapsules (NC). The acute lethal dose (LD100) of Hf.HCl experimentally observed was 200 mg/kg whereas the calculated LD50 was 154 mg/kg. In contrast, the LD100 for Hf-NC was 300 mg/ kg with a longer mean time to death than Hf.HCl. The calculated LD50 was 249 mg/kg for Hf-NC. The Hf entrapped in PCL NC presented a greater efficacy than PLA-PEG NC and than Hf solution in P. berghei-infected mice at 1 mg/kg. The cardiovascular parameters, ECG and arterial blood pressure, were evaluated in anaesthetized Wistar rats after the IV administration of a single, especially high dose (100 and 150 mg/kg) of halofantrine base loaded-nanocapsules (Hf-NC) or halofantrine chlorhydrate (Hf.HCl) solution. It was observed that Hf solution caused prolongation of the QT and PR intervals of the ECG; however, this effect was significantly (Pb0.001) reduced when Hf was administered entrapped in nanocapsules. The treatment with Hf.HCl induced a pronounced bradycardia and severe hypotension leading to death. The effect of Hf-NC upon heart rate was reduced from 58 to 75% for 100 and 150 mg/kg, respectively, when compared with Hf.HCl solution. These findings show that the encapsulation of halofantrine reduces the QT interval prolongation of ECG in rats and suggest that a modification of drug distribution was possible by using nanocapsules. Hf encapsulation was the main factor responsible for the significant reduction in cardiac toxicity observed.