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1.
Ground Water Monit Remediat ; 44(2): 101-117, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38846907

RESUMO

Understanding vapor intrusion (VI) temporal variability is key for the design of sampling strategies intended to assess reasonable maximum exposure of indoor air concentrations of volatile organic compounds (VOCs) as well as risk evaluation and mitigation planning. VI temporal variability has previously been shown to be dependent on the complex interactions of multiple independent variables-meteorological, hydrogeological, and human behavioral. Several meteorological variables, including barometric pressure, wind speed, and rainfall, are linked during tropical and extratropical storm events. High-frequency meteorological and indoor VOC data from a series of seven tropical storms and four extratropical storms were collected at a single industrial building with multiple heating, ventilation, and air conditioning (HVAC) zones. The storms and sampling zones showed a variety of effects on trichloroethylene (TCE) concentrations in indoor air. In one zone (supply room), increases in TCE concentrations often, but not always, closely coincided with decreasing barometric pressure, sustained wind speeds over 32 km/h (20 mph), and differential pressures indicating subslab to indoor flow. A second zone, in a restroom, did not show a consistent pattern of temporal correlation between meteorological factors and indoor air concentrations. While peak indoor air concentrations may be associated with the passage of cyclonic storms at some sampling locations, this does not appear to be generalizable to all sampling locations. The observed increase in indoor air concentration potentially attributable to these storms is typically less than an order of magnitude and the duration ranges from a day to a week.

2.
J Air Waste Manag Assoc ; 73(4): 258-270, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36729994

RESUMO

The default groundwater-to-indoor air attenuation factor (AF) of 10-3 (0.001) to assess the vapor intrusion (VI) pathway and generate VI screening levels for groundwater was developed by the United States Environmental Protection Agency (EPA) based on chlorinated volatile organic compound (VOC) indoor air and groundwater data collected in residential buildings and compiled in EPA's 2012 VI database. In their VI guidance published in 2015, EPA recognized that this default AF may be overly conservative for nonresidential buildings. In 2015, the Department of Defense (DoD) began developing a first-of-its-kind VI database to assess AFs at commercial and industrial buildings at DoD installations and support the development of alternative generic AF values. This database was expanded in 2019 to include 76 buildings at 22 DoD installations across the United States and is comparable in size to the EPA VI database. The DoD database includes chlorinated VOC data from groundwater and indoor air samples collected from multiple sampling zones within these buildings. Empirical groundwater-to-indoor air AFs were calculated using similar screening methods employed by EPA, including a source strength screen, to filter out potential background source contributions unrelated to VI. Analysis of indoor air-groundwater data pairs found that there is more attenuation occurring from groundwater to indoor air in DoD commercial and industrial buildings relative to residential buildings and that the DoD buildings' AFs are one to four orders of magnitude lower than EPA's residential-based default of 10-3. The results support the use of a generic groundwater AF of 10-4 (0.0001) to support VI assessment and develop groundwater screening levels specific to large commercial and industrial buildings as an alternative to the residential default AF.Implications: The use of groundwater-to-indoor air attenuation factors (AFs) is a key component of vapor intrusion (VI) pathway assessments and VI screening-level development for groundwater. Currently, the United States Environmental Protection Agency (EPA) and many state regulatory agencies use a default groundwater AF of 10-3 (0.001) based on chlorinated volatile organic compound (VOC) data collected in residential buildings. VI assessment data collected at Department of Defense (DoD) installations indicate that there is significantly more groundwater-to-indoor air attenuation occurring at DoD commercial and industrial buildings. For that reason, the default AF of 10-3 results in groundwater screening levels that are overestimating VI-related risks in these types of building. The DoD data support the use of a generic groundwater AF of 10-4 (0.0001) for conducting VI assessment and developing groundwater screening levels at large commercial and industrial buildings.


Assuntos
Poluição do Ar em Ambientes Fechados , Água Subterrânea , Compostos Orgânicos Voláteis , Estados Unidos , Poluição do Ar em Ambientes Fechados/análise , Compostos Orgânicos Voláteis/análise , Gases/análise
3.
Nat Commun ; 13(1): 6906, 2022 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-36372798

RESUMO

Daylight saving time (DST) consists in a one-hour advancement of legal time in spring offset by a backward transition of the same magnitude in fall. It creates a minimal circadian misalignment that could disrupt sleep and homoeostasis in susceptible individuals and lead to an increased incidence of pathologies and accidents during the weeks immediately following both transitions. How this shift affects mortality dynamics on a large population scale remains, however, unknown. This study examines the impact of DST on all-cause mortality in 16 European countries for the period 1998-2012. It shows that mortality decreases in spring and increases in fall during the first two weeks following each DST transition. Moreover, the alignment of time data around DST transition dates revealed a septadian mortality pattern (lowest on Sundays, highest on Mondays) that persists all-year round, irrespective of seasonal variations, in men and women aged above 40.


Assuntos
Ritmo Circadiano , Sono , Masculino , Humanos , Feminino , Estações do Ano , Incidência , Europa (Continente)/epidemiologia
4.
J Air Waste Manag Assoc ; 71(9): 1148-1158, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33989123

RESUMO

The default subslab soil gas (SSSG)-to-indoor air attenuation factor (AF) of 0.03 to assess the vapor intrusion (VI) pathway and generate VI screening levels for SSSG was developed by the United States Environmental Protection Agency (EPA) based on chlorinated volatile organic compound (VOC) indoor air and SSSG data collected in residential buildings and compiled in EPA's 2012 VI database. In their VI guidance published in 2015, EPA recognized that this default AF may be overly conservative for nonresidential buildings. In 2015, the Department of Defense (DoD) began developing a first-of-its-kind VI database to assess AFs at commercial and industrial buildings at DoD installations and support the development of alternative generic AF values. This database was expanded in 2019 to include 76 buildings at 22 DoD installations across the United States and is comparable in size to EPA's VI database. The DoD database includes chlorinated VOC data from SSSG and indoor air samples collected from multiple sampling zones within these buildings. Empirical SSSG-to-indoor air AFs were calculated using the same screening methods employed by EPA to filter out potential background source contributions unrelated to VI, including a source strength screen. Analysis of indoor air-SSSG data pairs found that there is substantially more attenuation occurring from SSSG to indoor air in DoD commercial and industrial buildings relative to residential buildings, and that the DoD buildings' AFs are one to three orders of magnitude lower than EPA's residential-based default of 0.03. The results support the use of a generic SSSG-to-indoor air AF of 10-3 (0.001) to support VI assessment and develop SSSG screening levels at large commercial and industrial buildings as an alternative to the residential default AF.Implications: The use of subslab soil gas (SSSG)-to-indoor air attenuation factors (AFs) is a key component of vapor intrusion (VI) pathway assessments and VI screening level development for SSSG. Currently, the United States Environmental Protection Agency (EPA) and many state regulatory agencies use a default AF of 0.03 based on chlorinated volatile organic compound (VOC) data collected in residential buildings. VI assessment data collected at Department of Defense (DoD) installations indicate that there is significantly more SSSG-to-indoor air attenuation occurring at DoD commercial and industrial buildings. For that reason, the default AF of 0.03 results in SSSG screening levels that are overestimating VI-related risks in these types of building. The DoD data support the use of a generic SSSG-to-indoor air AF of 10-3 (0.001) for conducting VI assessment and developing SSSG screening levels at large commercial and industrial buildings as an alternative to the residential default AF.


Assuntos
Poluição do Ar em Ambientes Fechados , Poluentes do Solo , Compostos Orgânicos Voláteis , Poluição do Ar em Ambientes Fechados/análise , Gases , Solo , Poluentes do Solo/análise , Estados Unidos , Compostos Orgânicos Voláteis/análise
5.
Sci Rep ; 8(1): 4797, 2018 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-29556068

RESUMO

Many therapeutic agents offer a low useful dose (dose responsible for efficacy)/useless dose (dose eliminated or responsible for toxicity) ratio, mainly due to the fact that therapeutic agents must ensure in one single object all the functions required to deliver the treatment, which leads to compromises in their physico-chemical design. Here we introduce the concept of priming the body to receive the treatment by uncorrelating these functions into two distinct objects sequentially administered: a nanoprimer occupying transiently the main pathway responsible for therapeutic agent limited benefit/risk ratio followed by the therapeutic agent. The concept was evaluated for different nature of therapeutic agents: For nanomedicines we designed a liposomal nanoprimer presenting preferential hepatic accumulation without sign of acute toxicity. This nanoprimer was able to increase the blood bioavailability of nanomedicine correlated with a lower hepatic accumulation. Finally this nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 tumor model when compared to the nanomedicine alone. Then, for small molecules we demonstrated the ability of a cytochrome inhibitor loaded nanoprimer to increase efficacy of docetaxel treatment. These results shown that specific nanoprimers could be designed for each family of therapeutic agents to answer to their specific needs.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Inibidores das Enzimas do Citocromo P-450/farmacologia , Docetaxel/farmacologia , Lipossomos/administração & dosagem , Nanomedicina/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Neoplasias da Mama/patologia , Proliferação de Células , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Docetaxel/farmacocinética , Feminino , Células HT29 , Humanos , Lipossomos/química , Camundongos , Distribuição Tecidual , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Eur J Radiol ; 97: 83-89, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29153373

RESUMO

PURPOSE: Evaluate concurrent Computer-Aided Detection (CAD) with Digital Breast Tomosynthesis (DBT) to determine impact on radiologist performance and reading time. MATERIALS AND METHODS: The CAD system detects and extracts suspicious masses, architectural distortions and asymmetries from DBT planes that are blended into corresponding synthetic images to form CAD-enhanced synthetic images. Review of CAD-enhanced images and navigation to corresponding planes to confirm or dismiss potential lesions allows radiologists to more quickly review DBT planes. A retrospective, crossover study with and without CAD was conducted with six radiologists who read an enriched sample of 80 DBT cases including 23 malignant lesions in 21 women. Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) compared the readings with and without CAD to determine the effect of CAD on overall interpretation performance. Sensitivity, specificity, recall rate and reading time were also assessed. Multi-reader, multi-case (MRMC) methods accounting for correlation and requiring correct lesion localization were used to analyze all endpoints. AUCs were based on a 0-100% probability of malignancy (POM) score. Sensitivity and specificity were based on BI-RADS scores, where 3 or higher was positive. RESULTS: Average AUC across readers without CAD was 0.854 (range: 0.785-0.891, 95% confidence interval (CI): 0.769,0.939) and 0.850 (range: 0.746-0.905, 95% CI: 0.751,0.949) with CAD (95% CI for difference: -0.046,0.039), demonstrating non-inferiority of AUC. Average reduction in reading time with CAD was 23.5% (95% CI: 7.0-37.0% improvement), from an average 48.2 (95% CI: 39.1,59.6) seconds without CAD to 39.1 (95% CI: 26.2,54.5) seconds with CAD. Per-patient sensitivity was the same with and without CAD (0.865; 95% CI for difference: -0.070,0.070), and there was a small 0.022 improvement (95% CI for difference: -0.046,0.089) in per-lesion sensitivity from 0.790 without CAD to 0.812 with CAD. A slight reduction in specificity with a -0.014 difference (95% CI for difference: -0.079,0.050) and a small 0.025 increase (95% CI for difference: -0.036,0.087) in recall rate in non-cancer cases were observed with CAD. CONCLUSIONS: Concurrent CAD resulted in faster reading time with non-inferiority of radiologist interpretation performance. Radiologist sensitivity, specificity and recall rate were similar with and without CAD.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Mamografia/normas , Neoplasias da Mama/patologia , Diagnóstico por Computador/métodos , Diagnóstico por Computador/normas , Métodos Epidemiológicos , Feminino , Humanos , Mamografia/métodos , Pessoa de Meia-Idade
7.
Int J Nanomedicine ; 12: 5537-5556, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28814868

RESUMO

Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of bio-compatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24 hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic-co-glycolic) acid (PLGA) with a hydrodynamic diameter of 63 nm, functionalized with galactosamine, showed efficient in vitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55).


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacologia , Portadores de Fármacos/química , Furocumarinas/farmacologia , Fígado/efeitos dos fármacos , Taxoides/farmacocinética , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A/química , Docetaxel , Portadores de Fármacos/farmacocinética , Feminino , Furocumarinas/química , Galactosamina/química , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Inativação Metabólica , Ácido Láctico/química , Fígado/metabolismo , Camundongos Nus , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Taxoides/administração & dosagem , Distribuição Tecidual
8.
Nanomedicine ; 13(5): 1715-1723, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28343019

RESUMO

Nanomedicines are mainly used as drug delivery systems; here we evaluate a new application - to inhibit a drug's metabolism thereby enhancing its effective dose. Micelles containing the natural furanocoumarin 6',7'-dihydroxybergamottin (DHB), a known CYP450 inhibitor, were developed to transiently block hepatic CYP450-mediated drug metabolism and increase the bioavailability of the oncology drug docetaxel. Administered in mice 24h prior to the drug, DHB-micelles enhanced antitumor efficacy in the tumor xenograft models HT-29 and MDA-MB-231, when compared to the drug alone. These DHB-micelles have similar composition to marketed docetaxel-micelles for human use. Despite not being optimized in terms of targeting hepatocytes, they do represent the first injectable example of nanosized metabolism-blocking agents and open the way for further work on such nanomedicines in man.


Assuntos
Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Micelas , Nanomedicina/métodos , Animais , Antineoplásicos , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450 , Humanos , Masculino , Camundongos
9.
Clin Cancer Res ; 23(4): 908-917, 2017 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-27998887

RESUMO

Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS).Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion.Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%-90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible.Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908-17. ©2016 AACR.


Assuntos
Nanopartículas/administração & dosagem , Recidiva Local de Neoplasia/radioterapia , Neoplasia Residual/radioterapia , Sarcoma/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Háfnio/administração & dosagem , Háfnio/química , Humanos , Masculino , Pessoa de Meia-Idade , Nanopartículas/química , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/patologia , Óxidos/administração & dosagem , Óxidos/química , Cuidados Pré-Operatórios , Dosagem Radioterapêutica , Radioterapia Adjuvante/efeitos adversos , Sarcoma/tratamento farmacológico , Sarcoma/patologia
10.
Ann Pathol ; 36(3): 166-73, 2016 Jun.
Artigo em Francês | MEDLINE | ID: mdl-27236350

RESUMO

OBJECTIVE: Since the last guidelines published by the French National Cancer Institute (INCa) and the learning society "Société française de sénologie et de pathologie mammaire (SFSPM)" in 2009 about diagnosis and management of ductal carcinoma in situ, new data raised issues about overdiagnosis and its consequences, overtreatment. Therefore, an update was necessary, to provide healthcare professionals up-to-date guidelines and study therapeutic desescalation in particular. METHODS: The clinical practice guidelines development process is based on systematic literature review and critical appraisal by a multidisciplinary experts workgroup. The recommendations are thus based on the best available evidence and experts agreement. Prior to publication, the guidelines are also reviewed by more than 100 independent practitioners in cancer care delivery. RESULTS: This article presents French guidelines about MRI and vacuum assisted breast biopsy indications for DCIS diagnosis and the management of low-grade DCIS.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Intraductal não Infiltrante/diagnóstico , Feminino , Humanos
11.
Biochem Biophys Res Commun ; 468(3): 471-5, 2015 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-26362175

RESUMO

Radio-enhancers, metal-based nanosized agents, could play a key role in oncology. They may unlock the potential of radiotherapy by enhancing the radiation dose deposit within tumors when the ionizing radiation source is 'on', while exhibiting chemically inert behavior in cellular and subcellular systems when the radiation beam is 'off'. Important decision points support the development of these new type of therapeutic agents originated from nanotechnology. Here, we discuss from an industry perspective, the interest of developing radio-enhancer agents to improve tumor control, the relevance of nanotechnology to achieve adequate therapeutic attributes, and present some considerations for their development in oncology.


Assuntos
Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/química , Nanocápsulas/química , Neoplasias/tratamento farmacológico , Radiossensibilizantes/administração & dosagem , Radioterapia/métodos , Animais , Humanos , Nanocápsulas/administração & dosagem , Radiossensibilizantes/química
12.
Br J Radiol ; 88(1054): 20150171, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26248871

RESUMO

Radiotherapy has a universal and predictable mode of action, that is, a physical mode of action consisting of the deposit of a dose of energy in tissues. Tumour cell damage is proportional to the energy dose. However, the main limitation of radiotherapy is the lack of spatial control of the deposition of energy, that is, it penetrates the healthy tissues, damages them and renders unfeasible delivery of an efficient energy dose when tumours are close to important anatomical structures. True nanosized radiation enhancers may represent a disruptive approach to broaden the therapeutic window of radiation therapy. They offer the possibility of entering tumour cells and depositing high amounts of energy in the tumour only when exposed to ionizing radiations (on/off activity). They may unlock the potential of radiation therapy by rendering the introduction of a greater energy dose, exactly within the tumour structure without passing through surrounding tissues feasible. Several nanosized radiation enhancers have been studied in in vitro and in vivo models with positive results. One agent has received the authorization to conduct clinical trials for human use. Opportunities to improve outcomes for patients receiving radiotherapy, to create new standards of care and to offer solutions to new patient populations are looked over here.


Assuntos
Nanopartículas/uso terapêutico , Neoplasias/radioterapia , Planejamento da Radioterapia Assistida por Computador/métodos , Humanos , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/tendências
13.
Nanomedicine ; 11(4): 983-92, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25724929

RESUMO

This is a perspective on the current state of development of nanomedicines in Europe. The view is expressed that a much higher translational success rate could be achieved, with rewards for all stakeholders, if researchers understood the industrial decision points required for new drugs. Getting a drug through the clinic will not help patients unless it is developable by industry. This article is written in the hope that it will help researchers and SMEs to decide where they are in the established process, whether they are making progress and to determine what to do next. It attempts to map the early stages from ideation to first (time) in man (FIM). FROM THE CLINICAL EDITOR: The field of nanomedicine has come a long way in the past decade. The overall dream of any researcher in this field remains the realization of concept to clinical product. In this paper, the authors outlined for the readers, the underlying problems and actions that need to be done, so that current challenges can be solved.


Assuntos
Atenção à Saúde/métodos , Atenção à Saúde/tendências , Nanomedicina/métodos , Nanomedicina/tendências , Europa (Continente) , Humanos
14.
Radiat Oncol ; 9: 150, 2014 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-24981953

RESUMO

BACKGROUND: Hafnium oxide, NBTXR3 nanoparticles were designed for high dose energy deposition within cancer cells when exposed to ionizing radiation. The purpose of this study was to assess the possibility of predicting in vitro the biological effect of NBTXR3 nanoparticles when exposed to ionizing radiation. METHODS: Cellular uptake of NBTXR3 nanoparticles was assessed in a panel of human cancer cell lines (radioresistant and radiosensitive) by transmission electron microscopy. The radioenhancement of NBTXR3 nanoparticles was measured by the clonogenic survival assay. RESULTS: NBTXR3 nanoparticles were taken up by cells in a concentration dependent manner, forming clusters in the cytoplasm. Differential nanoparticle uptake was observed between epithelial and mesenchymal or glioblastoma cell lines. The dose enhancement factor increased with increase NBTXR3 nanoparticle concentration and radiation dose. Beyond a minimum number of clusters per cell, the radioenhancement of NBTXR3 nanoparticles could be estimated from the radiation dose delivered and the radiosensitivity of the cancer cell lines. CONCLUSIONS: Our preliminary results suggest a predictable in vitro biological effect of NBTXR3 nanoparticles exposed to ionizing radiation.


Assuntos
Háfnio/farmacologia , Nanopartículas Metálicas/administração & dosagem , Óxidos/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/farmacologia , Sobrevivência Celular , Humanos , Técnicas In Vitro , Microscopia Eletrônica de Transmissão , Doses de Radiação , Células Tumorais Cultivadas , Raios X
16.
Anticancer Res ; 34(1): 443-53, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24403500

RESUMO

Since the discovery of cisplatin about 40 years ago, the design of innovative metal-based anticancer drugs is a growing area of research. Transition metal coordination complexes offer potential advantages over the more common organic-based drugs, including a wide range of coordination number and geometries, accessible redox states, tunability of the thermodynamics and kinetics of ligand substitution, as well as a wide structural diversity. Metal-based substances interact with cell molecular targets, affecting biochemical functions resulting in cancer cell destruction. Radionuclides are another way to use metals as anticancer therapy. The metal nucleus of the unstable radionuclide becomes stable by emitting energy. The biological effect in different tissues is obtained by the absorption of this energy from the radiation emitted by the radionuclide, the principal target generally agreed for ionizing radiations being DNA. A new area of clinical research is now emerging using the same experimental metal elements, but in a radically different manner: metals and metal oxides used as crystalline nanosized particles. In this field, man-made functionalized nanoparticles of high electron density and well-defined size and shape offer the possibility of entering cancer cells and depositing high amounts of energy in the tumor only when exposed to ionizing radiations (on/off activity). These nanoparticles, such as hafnium oxide engineered as 50 nm-sized spheres, functionalized with a negative surface (NBTXR3 nanoparticles), have been developed as selective radioenhancers, which represents a breakthrough approach for the local treatment of solid tumors. The properties of NBTXR3 nanoparticles, their chemistry, size, shape and surface charge, have been designed for efficient tumor cell uptake. NBTXR3 brings a physical mode of action, that of radiotherapy, within the cancer cells themselves. Physicochemical characteristics of NBTXR3 have demonstrated a very promising benefit-risk ratio for human healthcare across a broad non-clinical program. NBTXR3 has entered clinical development in therapy of advanced soft tissue sarcomas and head and neck cancer.


Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neoplasias/radioterapia , Radiossensibilizantes/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Prognóstico
17.
Phys Rev Lett ; 111(18): 187203, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-24237556

RESUMO

We have measured universal conductance fluctuations in the metallic spin glass Ag:Mn as a function of temperature and magnetic field. From this measurement, we can access the phase coherence time of the electrons in the spin glass. We show that this phase coherence time increases with both the inverse of the temperature and the magnetic field. From this, we deduce that decoherence mechanisms are still active even deep in the spin glass phase.

18.
Contrast Media Mol Imaging ; 8(2): 185-92, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23281291

RESUMO

Improved drug delivery control during chemotherapy has the potential to increase the therapeutic index. MRI contrast agent such as iron oxide nanoparticles can be co-encapsulated with drugs in nanocarrier liposomes allowing their tracking and/or visualization by MRI. Furthermore, the combination of a thermosensitive liposomal formulation with an external source of heat such as high intensity focused ultrasound guided by MR temperature mapping allows the controlled local release of the content of the liposome. MRI-guided high-intensity focused ultrasound (HIFU), in combination represents a noninvasive technique to generate local hyperthermia for drug release. In this study we used ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) encapsulated in thermosensitive liposomes to obtain thermosensitive magnetoliposomes (TSM). The transverse and longitudinal relaxivities of this MRI contrast agent were measured upon TSM membrane phase transition in vitro using a water bath or HIFU. The results showed significant differences for MRI signal enhancement and relaxivities before and after heating, which were absent for nonthermosensitive liposomes and free nanoparticles used as controls. Thus, incorporation of USPIO as MRI contrast agents into thermosensitive liposomes should, besides TSM tumor accumulation monitoring, allow the visualization of TSM membrane phase transition upon temperature elevation. In conclusion, HIFU under MR image guidance in combination with USPIO-loaded thermosensitive liposomes as drug delivery system has the potential for a better control of drug delivery and to increase the drug therapeutic index.


Assuntos
Preparações de Ação Retardada/química , Preparações de Ação Retardada/efeitos da radiação , Lipossomos/química , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/efeitos da radiação , Sonicação/métodos , Meios de Contraste/química , Meios de Contraste/efeitos da radiação , Temperatura Alta , Lipossomos/efeitos da radiação , Campos Magnéticos , Teste de Materiais , Som
19.
Future Oncol ; 8(9): 1167-81, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23030491

RESUMO

AIM: There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular high-energy dose deposit. MATERIALS & METHODS: Conventional methods were used, implemented in different ways, to explore interactions of these high-atomic-number nanoparticles and ionizing radiation with biological systems. RESULTS: Using the Monte Carlo simulation, these nanoparticles, when exposed to high-energy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation. CONCLUSION: These findings, supported by good tolerance, provide the basis for developing this new type of nanoparticle as a promising anticancer approach in human patients.


Assuntos
Háfnio/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/radioterapia , Óxidos/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos da radiação , Simulação por Computador , Endossomos/metabolismo , Endossomos/patologia , Feminino , Háfnio/efeitos adversos , Háfnio/farmacocinética , Humanos , Camundongos , Camundongos Nus , Modelos Biológicos , Método de Monte Carlo , Nanopartículas/efeitos adversos , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Óxidos/efeitos adversos , Óxidos/farmacocinética , Radiossensibilizantes/efeitos adversos , Radiossensibilizantes/farmacocinética , Radiografia , Carga Tumoral/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Photochem Photobiol B ; 100(1): 1-9, 2010 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-20456971

RESUMO

A new versatile hybrid nanocarrier has been designed using a "soft chemistry" synthesis, to efficiently encapsulate a photosensitizer - the protoporphyrin IX (Pp IX) - while preserving its activity intact in biological environment for advantageous use in photodynamic therapy (PDT). The synthesized Pp IX silica-based nanocarriers show to be spherical in shape and highly monodisperse with size extending from 10 nm up to 200 nm according to the synthesis procedure. Upon laser irradiation, the entrapped Pp IX shows to efficiently deliver reactive oxygen species (ROS) which are responsible for damaging tumor tissues. The ability of Pp IX silica-based nanocarriers to induce tumor cell death has been tested successfully in vitro. The stability of the Pp IX silica-based nanocarriers has been followed by UV-vis absorption and fluorescence emission in aqueous media and in 100% mouse serum media. The flexibility of the nanocarrier silica core has been examined as the key parameter to tune the Pp IX stability in biological environment. Indeed, an additional biocompatible inorganic surface coating performed on the Pp IX silica-based nanocarriers to produce an optimized bilayer coating demonstrates to significantly enhance the Pp IX stabilization in biological environments. Such versatile hybrid nanocarriers open new perspectives for PDT.


Assuntos
Portadores de Fármacos/síntese química , Nanopartículas/química , Fármacos Fotossensibilizantes/administração & dosagem , Protoporfirinas/administração & dosagem , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Camundongos , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/química , Espectrofotometria Ultravioleta
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