Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 386
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Br J Radiol ; 93(1106): 20180781, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31860336

RESUMO

OBJECTIVE: The aim of the study was to assess the feasibility of multitracer positron emission tomography (PET) imaging before and during chemoradiation and to evaluate the predictive value of image-based factors for outcome in locally advanced head and neck cancers treated with chemoradiation. METHODS: In the week prior to the treatment [18F]-2-flu-2-deoxy-D-glucose (FDG), [18F]-3'-flu-3'deoxythymidine (FLT) and [18F]-flumisonidazole (FMISO) imaging was performed. FLT scans were repeated at 14 and 28 Gy and FMISO at 36 Gy. Overall survival, disease-free survival and local control were correlated with subvolume parameters, and with tumour-to-muscle ratio for FMISO. For every tracer, total metabolic tumour volume was calculated. RESULTS: 33 patients were included. No correlation was found between pre-treatment maximum standardised uptake value for FDG, FLT, FMISO and outcomes. Tumour volume measured on initial CT scans and initial FLT volume correlated with disease-free survivall (p = 0.007 and 0.04 respectively). FDG and FLT metabolic tumour volumes correlated significantly with local control (p = 0.005 and 0.02 respectively). In multivariate Cox analysis only individual initial TMRmax correlated with overall survival. CONCLUSION: PET/CT imaging is a promising tool. However, various aspects of image analysis need further clinical validation in larger multicentre study employing uniform imaging protocol and standardisation, especially for hypoxia tracer. ADVANCES IN KNOWLEDGE: Monitoring of biological features of the tumour using multitracer PET modality seems to be a feasible option in daily clinical practice.Evaluation of hypoxic subvolumes is more patient dependent; thus, exploration of individual parameters of hypoxia is needed. tumour-to-muscle ratio seems to be the most promising so far.


Assuntos
Quimiorradioterapia/métodos , Neoplasias de Cabeça e Pescoço/terapia , Idoso , Antineoplásicos/administração & dosagem , Biomarcadores Tumorais/metabolismo , Cisplatino/administração & dosagem , Didesoxinucleosídeos/metabolismo , Intervalo Livre de Doença , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fluordesoxiglucose F18/metabolismo , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Misonidazol/análogos & derivados , Misonidazol/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Radiossensibilizantes/metabolismo , Resultado do Tratamento , Hipóxia Tumoral/efeitos dos fármacos
2.
Biomater Sci ; 7(8): 3450-3459, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31268067

RESUMO

Bismuth-containing nanoparticles (BNPs) are potential enhancers for tumor radiotherapy. Improving the bioavailability and developing synergistic therapeutic regimens benefit the drug transformation of BNPs. In the present study, we prepare a mesoporous silica-coated bismuth nanorod (BMSNR) camouflaged by a platelet membrane (PM). This biomimetic material is termed BMSNR@PM. The PM camouflage enhances the immune escape of the BMSNRs by lowering endocytosis by macrophages in the reticuloendothelial system. Additionally, the PM camouflage strengthens the material tumor-targeting capacity and leads to better radiotherapeutic efficacy compared with bare BMSNRs. Owing to the photothermal effect, BMSNR@PMs alters the cell cycle of 4T1 cancer cells post-treatment with 808 nm near-infrared irradiation (NIR). The proportions of S phase and G2/M phase cells decrease and increase, respectively, which explains the synergistic effect of NIR on BMSNR@PM-based radiotherapy. BMSNR@PMs efficiently eradicates cancer cells by the combined action of photothermal therapy (PTT) and radiotherapy in vivo and markedly improves the survival of 4T1-tumor-bearing mice. The synergistic therapeutic effect is superior to the outcomes of PTT and radiotherapy performed alone. Our study demonstrates a versatile bismuth-containing nanoplatform with tumor-targeting, immune escape, and radiosensitizing functionalities using an autologous cell membrane biomimetic concept that may promote the development of radiotherapy enhancers.


Assuntos
Bismuto/química , Bismuto/farmacologia , Plaquetas/citologia , Neoplasias da Mama/terapia , Membrana Celular/metabolismo , Nanotubos/química , Fototerapia , Sulfetos/química , Sulfetos/farmacologia , Animais , Bismuto/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Linhagem Celular Tumoral , Terapia Combinada , Endocitose , Feminino , Humanos , Macrófagos/metabolismo , Camundongos , Nanocompostos/química , Porosidade , Células RAW 264.7 , Radiossensibilizantes/química , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Dióxido de Silício/química , Sulfetos/metabolismo
3.
Anticancer Res ; 39(4): 1859-1867, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30952726

RESUMO

BACKGROUND: Proteins overexpressed in malignant tissues form important targets in the development of targeted therapeutics, and aptamers comprise an important affinity agent for therapy and drug delivery. In this study, aberrantly expressed mucin 1 glycoprotein was investigated as a therapeutic target in a breast cancer model. MATERIALS AND METHODS: In order to determine the feasibility of using an aptamer against mucin 1 (aptA) as carrier of the cytotoxic compound 1,10-phenanthroline to MCF-7 cells, as a potential radiosensitizer, was studied in experiments using circular dichroism and rhodamine labelling by fluorescent microscopy and flow cytometry. RESULTS: 1,10-Phenanthroline can be intercalated within aptA when complexed with Fe(II) ions, with dissociation constant (Kd) of 30 µM. The complex was subsequently capable of binding to and being internalised in MCF-7 breast cancer cells. CONCLUSION: aptA can carry 1,10-phenanthroline to cancer cells specifically and this complex represents a potential target-directed anticancer therapy.


Assuntos
Aptâmeros de Nucleotídeos/metabolismo , Neoplasias da Mama/metabolismo , Portadores de Fármacos , Endocitose , Mucina-1/metabolismo , Fenantrolinas/metabolismo , Radiossensibilizantes/metabolismo , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Estudos de Viabilidade , Feminino , Compostos Ferrosos/química , Humanos , Células MCF-7 , Mucina-1/genética , Fenantrolinas/química , Fenantrolinas/farmacologia , Radiossensibilizantes/farmacologia
4.
Biochem Biophys Res Commun ; 512(2): 392-398, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30902389

RESUMO

Radioresistance is a major challenge in lung cancer radiotherapy (RT), and consequently, new radiosensitizers are urgently needed. MicroRNAs (miRNAs) have been demonstrated to participate in many important cellular processes including radiosensitization. MiR-365 is dysregulated in non-small cell lung cancer (NSCLC) and is able to restrain the development of NSCLC. However, the relationship between miR-365 and radiosensitivities of NSCLC cells remains largely unknown. Here we reveal that overexpression of miR-365 is able to enhance the radiosensitivity of NSCLC cells through targeting CDC25A. We found that the expression level of miR-365 was positively correlated with the radiosensitivity of NSCLC cell lines. Furthermore, our results showed that overexpression of miR-365 could sensitize A549 cells to the irradiation. However, knockdown of miR-365 in H460 cells could act the converse manner. Mechanically, miR-365 was able to directly target 3'UTR of cell division cycle 25A (CDC25A) mRNA and reduce the expression of CDC25A at the levels of mRNA and protein. And we confirmed that miR-365 could increase the radiosensitivity of NSCLC cells by targeting CDC25A using in vitro and in vivo assays. Taken together, restoration of miR-365 expression enhances the radiosensitivity of NSCLC cells by suppressing CDC25A, and miR-365 could be used as a radiosensitizer for NSCLC therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/radioterapia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/radioterapia , MicroRNAs/genética , Tolerância a Radiação/genética , Fosfatases cdc25/antagonistas & inibidores , Fosfatases cdc25/genética , Regiões 3' não Traduzidas , Células A549 , Animais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Radiossensibilizantes/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Fosfatases cdc25/metabolismo
5.
Drug Deliv ; 26(1): 34-44, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30744436

RESUMO

The addition of temozolomide (TMZ) to radiotherapy (RT) improves survival of patients with glioblastoma (GBM). However, TMZ + RT causes excess toxicity in patients. In this study, we prepared angiopep-2 (A2) modified lipid-poly (hypoxic radiosensitized polyprodrug) nanoparticles for TMZ delivery (A2-P(MIs)25/TMZ) to achieve synergistic effects against glioma. This A2-P(MIs)25/TMZ display highly promising advantages: (1) a hydrophobic P-(MIs)25 core where poorly water-soluble TMZ can be encapsulated; (2) nitro groups of the hydrophobic P-(MIs)25 core that are converted into hydrophilic amino groups (P(NH2s)25) under low oxygen conditions to mimic the oxygen-increased sensitization to RT; (3) a lipid monolayer at the interface of the core and the shell to modify the A2 (a specific ligand for low-density lipoprotein receptor-related protein-1 (LRP-1), which are expressed in the blood-brain barrier (BBB) and human glioma cells), thereby enhancing the drug encapsulation efficiency in glioma. These nanoparticles appear as a promising and robust nanoplatforms for TMZ and hypoxic cell radiosensitization delivery.


Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Glioma/terapia , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Radiossensibilizantes/administração & dosagem , Temozolomida/administração & dosagem , Animais , Antineoplásicos Alquilantes/síntese química , Antineoplásicos Alquilantes/metabolismo , Linhagem Celular Tumoral , Terapia Combinada/métodos , Sistemas de Liberação de Medicamentos/métodos , Glioma/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Nus , Nanopartículas/química , Nanopartículas/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Radiossensibilizantes/síntese química , Radiossensibilizantes/metabolismo , Radioterapia/métodos , Temozolomida/síntese química , Temozolomida/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
6.
ChemMedChem ; 14(8): 823-832, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30707500

RESUMO

We developed new 10 B carriers for boron neutron capture therapy (BNCT) that can effectively transport and accumulate boron clusters into cells. These carriers consist of a lipopeptide, mercaptoundecahydrododecaborate (BSH), and a disulfide linker. The carriers were conceived according to the structure of pepducin, a membrane-penetrating lipopeptide targeting protease-activated receptor 1 (PAR1). To improve the membrane permeability of BSH, the structure was optimized using various lipopeptides possessing different peptides and lipid moieties. These synthesized lipopeptides were conjugated with BSH and evaluated for intracellular uptake using T98G glioblastoma cells. Among them, the most effectively incorporated and accumulated in the cells was compound 5 a, which contains a peptide of 13 residues derived from the intracellular third loop of PAR1 and a palmitoyl group. For further improvement of 10 B accumulation in cells, the introduction of an amine linker was investigated; intracellular uptake similar to that of 5 a was observed for compound 14, which has a piperazine linker. Both compounds 5 a and 14 showed a stronger radiosensitizing effect than BSH along on T98G cells under mixed-neutron beam irradiation. The results demonstrate that lipopeptide conjugation is effective for enhancing intracellular delivery and accumulation of BSH and improving the cytotoxic effect of BNCT.


Assuntos
Boroidretos/química , Boro/química , Desenho de Drogas , Lipopeptídeos/química , Radiossensibilizantes/síntese química , Compostos de Sulfidrila/química , Boro/metabolismo , Terapia por Captura de Nêutron de Boro , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Glioblastoma/radioterapia , Humanos , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia
7.
Colloids Surf B Biointerfaces ; 173: 564-570, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347383

RESUMO

Photodynamic therapy (PDT) as a promising noninvasive and effective treatment modality has been clinically approved for cancer therapy. However, the poor selectivity of tumor and hypoxia-induced resistance constrain PDT efficacy immensely. To further enhance PDT's potency, we developed a drug delivery system based on liposome combining PDT and chemotherapeutics. The lipophilic IR780 was loaded into the lipid bilayer while hydrophilic chemotherapeutic agent tirapazamine (TPZ) was encapsulated in the hydrophilic core. IR780 could generate reactive oxygen species and hypoxic microenvironment in local site because of the continuous consumption of oxygen, resulting in the TPZ encapsulated in the aqueous liposome chamber brings out TPZ radicals to cause DNA double-strand breaks and chromosome aberrations. In vivo studies demonstrated that the liposomes which encapsulate IR780 and TPZ showed great antitumor efficacy via combining photodynamic therapy with chemotherapy. Therefore, the investigation combines PDT and hypoxia-activated chemotherapy from the TPZ. It is a simple but effective liposome platform to achieve multiple synergistic antitumor efficacy and shows potential for clinical use.


Assuntos
Antineoplásicos/farmacologia , Terapia Combinada/métodos , Indóis/farmacologia , Lipossomos/efeitos da radiação , Neoplasias/terapia , Radiossensibilizantes/farmacologia , Tirapazamina/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Hipóxia/patologia , Indóis/química , Indóis/metabolismo , Raios Infravermelhos , Injeções Subcutâneas , Cinética , Lipossomos/administração & dosagem , Lipossomos/química , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Camundongos , Neoplasias/patologia , Fotoquimioterapia/métodos , Radiossensibilizantes/química , Radiossensibilizantes/metabolismo , Espécies Reativas de Oxigênio/agonistas , Espécies Reativas de Oxigênio/metabolismo , Tirapazamina/química , Tirapazamina/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação
8.
Radiat Res ; 191(1): 43-51, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30376411

RESUMO

Pharmacologic ascorbate (P-AscH-) is emerging as a promising adjuvant for advanced pancreatic cancer. P-AscH- generates hydrogen peroxide (H2O2), leading to selective cancer cell cytotoxicity. Catalytic manganoporphyrins, such as MnT4MPyP, can increase the rate of oxidation of P-AscH-, thereby increasing the flux of H2O2, resulting in increased cytotoxicity. We hypothesized that a multimodal treatment approach, utilizing a combination of P-AscH-, ionizing radiation and MnT4MPyP, would result in significant flux of H2O2 and pancreatic cancer cytotoxicity. P-AscH- with MnT4MPyP increased the rate of oxidation of P-AscH- and produced radiosensitization in all pancreatic cancer cell lines tested. Three-dimensional (3D) cell cultures demonstrated resistance to P-AscH-, radiation or MnT4MPyP treatments alone; however, combined treatment with P-AscH- and MnT4MPyP resulted in the inhibition of tumor growth, particularly when also combined with radiation. In vivo experiments using a murine model demonstrated an increased rate of ascorbate oxidation when combinations of P-AscH- with MnT4MPyP were given, thus acting as a radiosensitizer. The translational potential was demonstrated by measuring increased ascorbate oxidation ex vivo, whereby MnT4MPyP was added exogenously to plasma samples from patients treated with P-AscH- and radiation. Combination treatment utilizing P-AscH-, manganoporphyrin and radiation results in significant cytotoxicity secondary to enhanced ascorbate oxidation and an increased flux of H2O2. This multimodal approach has the potential to be an effective treatment for pancreatic ductal adenocarcinoma.


Assuntos
Ácido Ascórbico/metabolismo , Neoplasias Pancreáticas/metabolismo , Radiossensibilizantes/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Sinergismo Farmacológico , Espectroscopia de Ressonância de Spin Eletrônica , Humanos , Metaloporfirinas/uso terapêutico , Oxirredução , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/radioterapia
9.
Mol Ther ; 27(2): 355-364, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30503969

RESUMO

Radiotherapy is one of the most important treatment methods of tumors. However, the application of radiotherapy in hepatocellular carcinoma (HCC) is limited due to the low tolerance of normal liver cells for radiation and inherent radiation resistance in HCC. With the in-depth study of microRNAs (miRNAs) in tumor therapy, the regulation of tumor radiosensitivity by miRNAs has been a research hotspot in recent years. In the present study, the expression of miR-621 was lower in HCC tissues and cells, and such low expression of miR-621 was associated with poor prognosis in HCC patients. In addition, in vivo and in vitro assays confirmed that the high expression of miR-621 could significantly enhance the radiosensitivity of HCC. Moreover, the expressions of miR-621 and SETDB1 in HCC tissues were negatively correlated. Dual-luciferase reporter assays indicated that miR-621 could directly target the 3' UTR of SETDB1. In addition, miR-621 enhanced the radiosensitivity of HCC cells via directly inhibiting SETDB1. Besides, the miR-621 and/or SETDB1 axis improved the radiosensitivity of HCC cells via activating the p53-signaling pathway. Taken together, miR-621 and/or SETDB1 might be used as a novel therapeutic target for the treatment of HCC.


Assuntos
Carcinoma Hepatocelular/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias Hepáticas/metabolismo , MicroRNAs/metabolismo , Micro-Ondas , Radiossensibilizantes/metabolismo , Animais , Carcinoma Hepatocelular/radioterapia , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/efeitos da radiação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células Hep G2 , Histona-Lisina N-Metiltransferase/genética , Humanos , Neoplasias Hepáticas/radioterapia , Camundongos , Camundongos Nus , MicroRNAs/genética , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação
10.
Biomed Pharmacother ; 109: 2173-2181, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30551474

RESUMO

Breast cancer resistance protein (BCRP) belongs to the family of ATP-binding cassette (ABC) transporters, overexpression of which can confer a multidrug-resistant phenotype in cancer cells and tumors. BCRP mediates efflux of numerous xenobiotics, including various chemotherapeutic agents and photosensitizers. Hypericin (HY) is a naturally-occurring photosensitizer synthesized by plants of the genus Hypericum. Our recently published results indicate that accumulation of HY in cancer cells of different tissue origin can be affected mostly by BCRP. Considering all known facts, the main goal of this study was to verify whether not only HY accumulation but also toxicity of HY-mediated photodynamic therapy (PDT) can be affected by the presence of some ABC transporters. To specifically prove our hypothesis, we used an experimental model of human leukemia cell lines differing in the expression level of the main drug efflux transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and BCRP. The lowest HY accumulation, and consequently the highest resistance to HY-PDT, was found in cells overexpressing BCRP. Moreover, pretreatment with BCRP inhibitor Ko143 significantly increased HY accumulation and sensitized cells to HY-PDT. Therefore, our findings represent direct evidence that BCRP is the nemesis of HY accumulation and toxicity of HY-PDT. Thus, we should emphasize that individualized screening for BCRP expression and activity may represent a useful tool for prediction of HY-mediated photodynamic diagnosis (PDD) or PDT effectiveness.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Neoplasias da Mama/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Perileno/análogos & derivados , Fotoquimioterapia , Radiossensibilizantes/metabolismo , Antineoplásicos/metabolismo , Antineoplásicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Células HL-60 , Humanos , Perileno/antagonistas & inibidores , Perileno/metabolismo , Perileno/toxicidade , Fotoquimioterapia/efeitos adversos , Radiossensibilizantes/toxicidade
11.
Nanomedicine (Lond) ; 13(22): 2917-2937, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30427254

RESUMO

AIM: To identify new mechanisms responsible for the radiosensitization effect of gold nanoparticles (GNPs). MATERIALS & METHODS: A549 lung carcinoma cells were incubated with 10-nm GNPs during 6 or 24 h before to be exposed to 25 keV/µm protons or 225 kV x-rays. RESULTS: GNP incubation led to a time-dependent mitochondria membrane depolarization, oxidative stress and to x-ray and proton radiosensitization. Moreover, a marked inhibition of thioredoxin reductase was observed. Irradiation of cells invalidated for thioredoxin reductase evidenced a radiosensitization effect, suggesting that this enzyme is a potential GNP target. CONCLUSION: We suggest that GNPs play a radiosensitizer role by weakening detoxification systems. Altogether, these results open up promising novel strategies for the development of nanotechnologies associated to radiotherapy.


Assuntos
Ouro/química , Nanopartículas Metálicas/química , Radiossensibilizantes/metabolismo , Tiorredoxina Dissulfeto Redutase/metabolismo , Células A549 , Proliferação de Células/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Humanos , Estresse Oxidativo/efeitos dos fármacos , Tamanho da Partícula , Prótons , Radioterapia/métodos , Propriedades de Superfície , Raios X
12.
J Biomed Opt ; 23(6): 1-6, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29873205

RESUMO

Tumor hypoxia is a critical indicator of poor clinical outcome in patients with cancers of the breast, cervix, and oral cavity. The ability to noninvasively and reliably monitor tumor oxygenation both prior to and during therapy can aid in identifying poor treatment response earlier than is currently possible and lead to effective changes in treatment regimen. Diffuse reflectance spectroscopy (DRS) has been used in several studies to measure tissue scattering, total hemoglobin content (THb), and vascular oxygenation (sO2) in tissue. In this study, we validate in vivo DRS-based measurements of vascular oxygenation using immunohistochemical staining of tumor hypoxia using pimonidazole, an established hypoxia marker. Using tumor xenografts grown from two different head and neck cell lines-UM-SCC-22B and UM-SCC-47-we demonstrate statistically significant negative correlations between tumor hypoxic fraction (HF) and THb (r = - 0.45; p = 0.04) and sO2 (r = - 0.50; p = 0.02). In addition, we also found a statistically significant positive correlation between HF and mean reduced scattering coefficient (r = 0.60; p = 0.005). Our results demonstrate that DRS-based measures of sO2 can provide reliable indirect measurements of tumor hypoxia that can be of significant utility in preclinical and clinical studies.


Assuntos
Técnicas Biossensoriais/métodos , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Oxigênio/análise , Análise Espectral/métodos , Hipóxia Tumoral/fisiologia , Animais , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Hemoglobinas/metabolismo , Humanos , Camundongos , Camundongos Nus , Nitroimidazóis/metabolismo , Radiossensibilizantes/metabolismo , Células Tumorais Cultivadas
13.
Brain Struct Funct ; 223(7): 3463-3471, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29936552

RESUMO

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by the presence of antiphospholipid antibodies, which may trigger vascular thrombosis with consecutive infarcts. However, cognitive dysfunctions representing one of the most commonest neuropsychiatric symptoms are frequently present despite the absence of any ischemic brain lesions. Data on the structural and functional basis of the neuropsychiatric symptoms are sparse. To examine the effect of APS on hippocampal neurogenesis and on white matter, we induced experimental APS (eAPS) in adult female Balb/C mice by immunization with ß2-glycoprotein 1. To investigate cell proliferation in the dentate gyrus granular cell layer (DG GCL), eAPS and control mice (n = 5, each) were injected with 5-bromo-2'-deoxyuridine (BrdU) once a day for 10 subsequent days. Sixteen weeks after immunization, eAPS resulted in a significant reduction of BrdU-positive cells in the DG GCL compared to control animals. However, double staining with doublecortin and NeuN revealed a largely preserved neurogenesis. Ultrastructural analysis of corpus callosum (CC) axons in eAPS (n = 6) and control mice (n = 7) revealed no significant changes in CC axon diameter or g-ratio. In conclusion, decreased cellular proliferation in the hippocampus of eAPS mice indicates a limited regenerative potential and may represent one neuropathological substrate of cognitive changes in APS while evidence for alterations of white matter integrity is lacking.


Assuntos
Síndrome Antifosfolipídica/induzido quimicamente , Síndrome Antifosfolipídica/patologia , Proliferação de Células , Giro Denteado/patologia , Animais , Anticorpos Antifosfolipídeos/metabolismo , Autoantígenos/farmacologia , Escala de Avaliação Comportamental , Bromodesoxiuridina/administração & dosagem , Bromodesoxiuridina/metabolismo , Diferenciação Celular/fisiologia , Corpo Caloso/ultraestrutura , Modelos Animais de Doenças , Feminino , Fluorescência , Camundongos , Camundongos Endogâmicos BALB C , Neurogênese , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/metabolismo , beta 2-Glicoproteína I/farmacologia
14.
J Pharm Pharmacol ; 70(9): 1152-1163, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29943465

RESUMO

OBJECTIVES: Chlorin e6 is a poorly water-soluble photoactive drug. Its monomers form aggregates at the tumour physiological pH, which drastically reduces its photodynamic efficacy. This study aimed to improve the dissolution rate and photodynamic efficacy of chlorin e6 by nanosuspension formulation using biodegradable sucrose esters as drug carrier. METHODS: A modified emulsion-solvent diffusion method was used to prepare the nanosuspension, where amount of Ce6, ratio of sucrose monopalmitate to sucrose monolaurate as carrier and ratio of dichloromethane to acetone as solvent, were varied using central composite design. Particle size, zeta potential, encapsulation efficiency and in vitro drug release characteristics of the nanosuspensions were evaluated. The formulation was optimised by response surface methodology and its photodynamic efficacy evaluated. KEY FINDINGS: The optimised nanosuspension had mean particle size of ~200 nm, 88% drug encapsulation efficiency and faster drug release compared to pure Ce6. Spectroscopic studies showed that Ce6 exists in monomeric form in the carrier, which facilitated a remarkable increase in cellular uptake, in vitro singlet oxygen generation and cytotoxicity to oral squamous carcinoma cells. CONCLUSIONS: The dissolution rate and photodynamic efficacy of Ce6 were markedly improved by formulating the drug as a nanosuspension with sucrose esters as drug carrier.


Assuntos
Portadores de Fármacos/metabolismo , Nanosferas/metabolismo , Fármacos Fotossensibilizantes/metabolismo , Porfirinas/metabolismo , Radiossensibilizantes/metabolismo , Sacarose/metabolismo , Linhagem Celular Tumoral , Portadores de Fármacos/química , Composição de Medicamentos , Ésteres , Humanos , Nanosferas/química , Fármacos Fotossensibilizantes/química , Porfirinas/química , Radiossensibilizantes/química , Solubilidade , Sacarose/análogos & derivados , Sacarose/química , Difração de Raios X/métodos
15.
Artif Cells Nanomed Biotechnol ; 46(sup2): 836-846, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29741418

RESUMO

INTRODUCTION: Recently it has been shown that radiation dose enhancement could be achievable in radiotherapy using nanoparticles (NPs). In this study, evaluation was made to determine efficiency of gold-silica shell-core NP in megavoltage irradiation of MCF7 breath cancer cells. MATERIALS AND METHODS: Gold-silicon oxide shell-core NPs were obtained by conjugation of gold NP with amine or thiol functionalized silica NPs (AuN@SiO2 and AuS@SiO2). Cellular uptake and cytotoxicity of NPs were examined by fluorescent microscopy and MTT assay, respectively. MCF-7 breast cancer cells were treated with both NPs and irradiation was made with X-ray energies of 6 and 18 MV to the absorbed dose of 2, 4 and 8 Gy using Simense linear accelerator. The efficiency of radiation therapy was then evaluated by MTT and Brdu assay, DAPI staining and cell cycle analysis. RESULTS: TEM images indicated that synthesized NPs had average diameter of 25 nm. Cellular uptake demonstrated that the internalization of AuS@SiO2 and AuN@SiO2 NPs amounted to 18% and 34%, 3 h post treatment, respectively. Nontoxicity of prepared NPs on MCF-7 cells was proved by MTT and Brdu assays as well as DAPI staining and cell cycle studies. The highest enhancement in radiation dose was observed in the cells that irradiated with radiation energy of 18 MV and absorbed of 8 Gy at NPs concentration of 200 ppm. The Brdu findings revealed that the cytotoxicity and apoptosis on MCF-7 cells are dose dependent with a significantly more death in AuN@SiO2 (amine) exposed cells (p < .05). Analysis also revealed interruption in cell cycle by demonstrating lack of cells, in S phase in amine treated cells (AuN@SiO2) at given dose of 8 Gy using 18 MV X-ray in comparison to thiol treated cells. CONCLUSIONS: Based on the results of the study it can be concluded that the gold-silicon oxide shell-core NPs could play an effective role in radiotherapy of MCF-7 breast cancer cells.


Assuntos
Neoplasias da Mama/patologia , Ouro/química , Nanopartículas Metálicas/química , Nanopartículas/química , Dióxido de Silício/química , Dióxido de Silício/farmacologia , Apoptose/efeitos dos fármacos , Transporte Biológico , Neoplasias da Mama/radioterapia , Ciclo Celular/efeitos dos fármacos , Humanos , Espaço Intracelular/metabolismo , Células MCF-7 , Tamanho da Partícula , Radiossensibilizantes/química , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Dióxido de Silício/metabolismo
17.
Pharmacol Res ; 120: 43-50, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28288939

RESUMO

Afatinib is a highly selective, irreversible inhibitor of EGFR and HER-2. It is orally administered for the treatment of patients with EGFR mutation-positive types of metastatic NSCLC. We investigated whether afatinib is a substrate for the multidrug efflux transporters ABCB1 and ABCG2 and whether these transporters influence oral availability and brain and other tissue accumulation of afatinib. We used in vitro transport assays to assess human (h)ABCB1-, hABCG2- or murine (m)Abcg2-mediated transport of afatinib. To study the single and combined roles of Abcg2 and Abcb1a/1b in oral afatinib disposition, we used appropriate knockout mouse strains. Afatinib was transported well by hABCB1, hABCG2 and mAbcg2 in vitro. Upon oral administration of afatinib, Abcg2-/-, Abcb1a/1b-/- and Abcb1a/1b-/-;Abcg2-/- mice displayed a 4.2-, 2.4- and 7-fold increased afatinib plasma AUC0-24 compared with wild-type mice. Abcg2-deficient strains also displayed decreased afatinib plasma clearance. At 2h, relative brain accumulation of afatinib was not significantly altered in the single knockout strains, but 23.8-fold increased in Abcb1a/1b-/-;Abcg2-/- mice compared to wild-type mice. Abcg2 and Abcb1a/1b restrict oral availability and brain accumulation of afatinib. Inhibition of these transporters may therefore be of clinical importance for patients with brain (micro)metastases positioned behind an intact blood-brain barrier.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Proteínas de Neoplasias/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/farmacocinética , Radiossensibilizantes/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Administração Oral , Afatinib , Animais , Transporte Biológico , Cães , Receptores ErbB/antagonistas & inibidores , Feminino , Humanos , Células Madin Darby de Rim Canino , Camundongos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/metabolismo , Quinazolinas/administração & dosagem , Quinazolinas/metabolismo , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Distribuição Tecidual
18.
Biochem Biophys Res Commun ; 486(2): 307-313, 2017 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-28300555

RESUMO

Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined. Moreover, the small molecule DNA-PKCS inhibitor, KU60648, was investigated as a radiosensitizing strategy for osteosarcoma cells in vitro. DNA-PKCS was consistently expressed in the osteosarcoma tissue specimens and cell lines studied. Additionally, KU60648 effectively sensitized two of those osteosarcoma cell lines (143B cells by 1.5-fold and U2OS cells by 2.5-fold). KU60648 co-treatment also altered cell cycle distribution and enhanced DNA damage. Cell accumulation at the G2/M transition point increased by 55% and 45%, while the percentage of cells with >20 γH2AX foci were enhanced by 59% and 107% for 143B and U2OS cells, respectively. These results indicate that the DNA-PKCS inhibitor, KU60648, is a promising radiosensitizing agent for osteosarcoma.


Assuntos
Neoplasias Ósseas/terapia , Cromonas/farmacologia , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Proteínas Nucleares/antagonistas & inibidores , Osteossarcoma/terapia , Inibidores de Proteínas Quinases/farmacologia , Radiossensibilizantes/farmacologia , Neoplasias Ósseas/enzimologia , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Cromonas/química , Cromonas/metabolismo , Dano ao DNA , Proteína Quinase Ativada por DNA/genética , Proteína Quinase Ativada por DNA/metabolismo , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos da radiação , Raios gama/uso terapêutico , Histonas/genética , Histonas/metabolismo , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Osteossarcoma/enzimologia , Osteossarcoma/genética , Osteossarcoma/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Radiossensibilizantes/química , Radiossensibilizantes/metabolismo , Análise de Sequência de RNA
19.
Radiat Res ; 187(2): 147-160, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28085639

RESUMO

Gold nanoparticles (AuNPs) and cisplatin have been explored in concomitant chemoradiotherapy, wherein they elicit their effects by distinct and overlapping mechanisms. Cisplatin is one of the most frequently utilized radiosensitizers in the clinical setting; however, the therapeutic window of cisplatin-aided chemoradiotherapy is limited by its toxicity. The goal of this study was to determine whether AuNPs contribute to improving the treatment response when combined with fractionated cisplatin-based chemoradiation in both in vitro and in vivo models of triple-negative breast cancer (MDA-MB-231Luc+). Cellular-targeting AuNPs with receptor-mediated endocytosis (AuNP-RME) in vitro at a noncytotoxic concentration (0.5 mg/ml) or cisplatin at IC25 (12 µM) demonstrated dose enhancement factors (DEFs) of 1.25 and 1.14, respectively; the combination of AuNP-RME and cisplatin resulted in a significant DEF of 1.39 in vitro. Transmission electron microscopy (TEM) images showed effective cellular uptake of AuNPs at tumor sites 24 h after intratumoral infusion. Computed tomography (CT) images demonstrated that the intratumoral levels of gold remained stable up to 120 h after infusion. AuNPs (0.5 mg gold per tumor) demonstrated a radiation enhancement effect that was equivalent to three doses of cisplatin at IC25 (4 mg/kg), but did not induce intrinsic toxicity or increased radiotoxicity. Results from this study suggest that AuNPs are the true radiosensitizer in these settings. Importantly, AuNPs enhance the treatment response when combined with cisplatin-based fractionated chemoradiation. This combination of AuNPs and cisplatin provides a promising approach to improving the therapeutic ratio of fractionated radiotherapy.


Assuntos
Quimiorradioterapia , Cisplatino/farmacologia , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas , Neoplasias de Mama Triplo Negativas/patologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Transporte Biológico/efeitos da radiação , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Ouro/metabolismo , Humanos , Camundongos , Radiossensibilizantes/química , Radiossensibilizantes/metabolismo , Radiossensibilizantes/farmacologia , Neoplasias de Mama Triplo Negativas/terapia
20.
Oncol Rep ; 36(5): 2946-2950, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27665739

RESUMO

In this study, we compared the microRNA (miRNA) profiles of a control and X-ray- and carbon ion beam-resistant cells to identify miRNAs that can be used as radiosensitizers and biomarkers. Mouse squamous cell carcinoma line NR-S1, its X-ray-resistant derivative X60, and its carbon ion beam­resistant derivative C30 were subjected to miRNA microarray analysis. Expression of miRNAs shown to be upregulated or downregulated in the microarray analysis was confirmed by qRT-PCR. Downregulated miRNAs were overexpressed in human pancreatic cancer cell lines PANC1 and MIA PaCa-2, and the resulting cells were tested for radiosensitivity using colony-forming and sphere-forming assays. Of 1,265 miRNAs analyzed, 4 were downregulated and 11 were upregulated in X-ray-resistant and carbon ion beam-resistant cells. Two of the downregulated miRNAs, miR-196 and miR-374, were selected for overexpression in PANC1 and MIA PaCa-2 cells. Overexpression of miR-374 sensitized PANC-1 and MIA PaCa-2 cells toward carbon ion beam radiation. miRNA miR-374 has the potential to be a new radiosensitizer for carbon ion beam radiotherapy and a new biomarker to determine the optimal treatment for cancer.


Assuntos
Biomarcadores Tumorais/genética , MicroRNAs/genética , Neoplasias Pancreáticas/radioterapia , Tolerância a Radiação/genética , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Radioterapia com Íons Pesados , Humanos , Camundongos , MicroRNAs/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Radiossensibilizantes/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA