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1.
Genes (Basel) ; 10(4)2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-31013756

RESUMO

A growing tumor is constantly secreting inflammatory chemokines and cytokines that induce release of immature myeloid cells, including myeloid-derived suppressor cells (MDSCs) and macrophages, from the bone marrow. These cells not only promote tumor growth, but also prepare distant organs for tumor metastasis. On the other hand, the myeloid-derived cells also have phagocytic potential, and can serve as vehicles for drug delivery. We have previously identified thioaptamers that bind a subset of MDSCs with high affinity and specificity. In the current study, we applied one of the thioaptamers as a probe to track myeloid cell distribution in the bone, liver, spleen and tumor in multiple murine models of breast cancer including the 4T1 syngeneic model and MDA-MB-231 and SUM159 xenograft models. Information generated from this study will facilitate further understanding of tumor growth and metastasis, and predict biodistribution patterns of cell-mediated drug delivery.


Assuntos
Osso e Ossos/citologia , Neoplasias da Mama/metabolismo , Rastreamento de Células/métodos , Fígado/citologia , Células Supressoras Mieloides/metabolismo , Baço/citologia , Animais , Aptâmeros de Nucleotídeos/administração & dosagem , Osso e Ossos/metabolismo , Linhagem Celular Tumoral , Feminino , Granulócitos/metabolismo , Humanos , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , Transplante de Neoplasias , Baço/metabolismo , Distribuição Tecidual
2.
Cell Death Dis ; 9(10): 986, 2018 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-30250075

RESUMO

Lung cancer is the leading cause of death in the United States, with non-small cell lung cancers (NSCLC) accounting for 85% of all cases. By analyzing the expression profile of the pro-apoptotic and anti-apoptotic proteins, we have assigned NSCLCs into two distinct groups. While single agent treatment with the BCL-2/BCL-xL/BCL-w inhibitor ABT-263 (navitoclax) did not trigger apoptosis in either group, cells with a moderate to high level of MCL-1 expression were sensitive to ABT-263 treatment when MCL-1 expression was suppressed with a gene-specific siRNA. In contrast, those with a low MCL-1 expression did not undergo apoptosis upon combination treatment with ABT-263 and MCL-1 siRNA. Further studies revealed that cells with a low MCL-1 expression had low mitochondrial priming, and treatment with the chemotherapy drug docetaxel raised the mitochondrial priming level and consequently sensitized cells to ABT-263. These results establish a rationale for molecular profiling and a therapeutic strategy to treat NSCLC patients with pro-apoptotic anti-cancer drugs based on their MCL-1 expression level.


Assuntos
Compostos de Anilina/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Docetaxel/farmacologia , Neoplasias Pulmonares/metabolismo , Proteínas de Membrana/metabolismo , Sulfonamidas/farmacologia , Proteína bcl-X/metabolismo , Células A549 , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Polaridade Celular , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Técnicas de Inativação de Genes , Humanos , Neoplasias Pulmonares/patologia , Proteínas de Membrana/genética , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Transfecção
3.
J Control Release ; 268: 92-101, 2017 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-29042320

RESUMO

Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS.


Assuntos
Antineoplásicos/administração & dosagem , Arsenicais/administração & dosagem , Azacitidina/análogos & derivados , Síndromes Mielodisplásicas/tratamento farmacológico , Nanopartículas/administração & dosagem , Óxidos/administração & dosagem , Alendronato/administração & dosagem , Alendronato/química , Alendronato/farmacocinética , Alendronato/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Trióxido de Arsênio , Arsenicais/química , Arsenicais/farmacocinética , Arsenicais/uso terapêutico , Azacitidina/administração & dosagem , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Osso e Ossos/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Decitabina , Camundongos Transgênicos , Síndromes Mielodisplásicas/metabolismo , Nanopartículas/química , Nanopartículas/uso terapêutico , Óxidos/química , Óxidos/farmacocinética , Óxidos/uso terapêutico , Fosfatidiletanolaminas/administração & dosagem , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Fosfatidiletanolaminas/uso terapêutico , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/uso terapêutico , Distribuição Tecidual
4.
Adv Healthc Mater ; 6(13)2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28402587

RESUMO

Atherosclerosis is an inflammatory disorder characterized by the progressive thickening of blood vessel walls eventually resulting in acute vascular syndromes. Here, intravenously injectable hybrid nanoconstructs are synthesized for tempering immune cell inflammation locally and systemically. Lipid and polymer chains are nanoprecipitated to form 100 nm spherical polymeric nanoconstructs (SPNs), loaded with methotrexate (MTX) and subsequently labeled with Cu64 and fluorescent probes for combined nuclear/optical imaging. Upon engulfment into macrophages, MTX SPNs intracellularly release their anti-inflammatory cargo significantly lowering the production of proinflammatory cytokine (interleukin 6 and tumor necrosis factor α) already at 0.06 mg mL-1 of MTX. In ApoE-/- mice, fed with high-fat diet up to 17 weeks, nuclear and optical imaging demonstrates specific accumulation of SPNs within lipid-rich plaques along the arterial tree. Histological analyses confirm SPN uptake into macrophages residing within atherosclerotic plaques. A 4-week treatment with biweekly administration of MTX SPNs is sufficient to reduce the plaque burden in ApoE-/- mice by 50%, kept on high-fat diet for 10 weeks. Systemic delivery of MTX to macrophages via multifunctional, hybrid nanoconstructs constitutes an effective strategy to inhibit atherosclerosis progression and induce, potentially, the resorption of vascular lesions.


Assuntos
Apolipoproteínas E/deficiência , Aterosclerose/tratamento farmacológico , Metotrexato , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Radioisótopos de Cobre/química , Radioisótopos de Cobre/farmacocinética , Radioisótopos de Cobre/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Interleucina-6/metabolismo , Metotrexato/química , Metotrexato/farmacocinética , Metotrexato/farmacologia , Camundongos , Camundongos Knockout , Imagem Óptica/métodos , Fator de Necrose Tumoral alfa/metabolismo
5.
Nanomaterials (Basel) ; 7(4)2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28350351

RESUMO

Multiple formulations of iron oxide nanoparticles (IONPs) have been proposed for enhancing contrast in magnetic resonance imaging (MRI) and for increasing efficacy in thermal ablation therapies. However, insufficient accumulation at the disease site and low magnetic performance hamper the clinical application of IONPs. Here, 20 nm iron oxide nanocubes were assembled into larger nanoconstructs externally stabilized by a serum albumin coating. The resulting assemblies of nanocubes (ANCs) had an average diameter of 100 nm and exhibited transverse relaxivity (r2 = 678.9 ± 29.0 mM‒1·s‒1 at 1.41 T) and heating efficiency (specific absorption rate of 109.8 ± 12.8 W·g‒1 at 512 kHz and 10 kA·m‒1). In mice bearing glioblastoma multiforme tumors, Cy5.5-labeled ANCs allowed visualization of malignant masses via both near infrared fluorescent and magnetic resonance imaging. Also, upon systemic administration of ANCs (5 mgFe·kg‒1), 30 min of daily exposure to alternating magnetic fields for three consecutive days was sufficient to halt tumor progression. This study demonstrates that intravascular administration of ANCs can effectively visualize and treat neoplastic masses.

6.
J Control Release ; 170(3): 460-8, 2013 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-23791978

RESUMO

PPARγ nuclear receptor agonists have been shown to attenuate macrophage inflammatory responses implicated in the metabolic complications of obesity and in atherosclerosis. However, PPARγ agonists currently in clinical use, including rosiglitazone (RSG), are often associated with severe side effects that limit their therapeutic use. Here, 200nm PLGA/PVA nanospheres were formulated for the systemic delivery of RSG specifically to macrophages. RSG was encapsulated with over 50% efficiency in the hydrophobic PLGA core and released specifically within the acidifying macrophage phagosomes. In bone marrow derived macrophages, RSG-loaded nanoparticles (RSG-NPs) induce a dose dependent upregulation (1.5 to 2.5-fold) of known PPARγ target genes, with maximal induction at 5µM; and downregulate the expression of genes related to the inflammatory process, with a maximum effect at 10µM. In Ldlr(-/-) mice fed high fat diet, treatment with RSG-NPs alleviated inflammation in white adipose tissue and liver but, unlike treatment with free RSG, did not alter genes associated with lipid metabolism or cardiac function, indicating a reduction in the RSG side effect profile. These biocompatible, biodegradable RSG-NPs represent a preliminary step towards the specific delivery of nuclear receptor agonists for the treatment of macrophage-mediated inflammatory conditions associated with obesity, atherosclerosis and other chronic disease states.


Assuntos
Anti-Inflamatórios/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inflamação/tratamento farmacológico , Nanosferas/administração & dosagem , Obesidade/tratamento farmacológico , Tiazolidinedionas/administração & dosagem , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Anti-Inflamatórios/química , Células da Medula Óssea/citologia , Linhagem Celular , Células Cultivadas , Regulação da Expressão Gênica , Hepatite/tratamento farmacológico , Hepatite/metabolismo , Hipoglicemiantes/química , Inflamação/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Nanosferas/química , Obesidade/metabolismo , Álcool de Polivinil/química , Receptores de LDL/deficiência , Receptores de LDL/genética , Rosiglitazona , Tiazolidinedionas/química
7.
Arterioscler Thromb Vasc Biol ; 32(12): 2839-46, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23023374

RESUMO

OBJECTIVE: To determine the impact of hematopoietic deletion of nuclear factor- (erythroid-derived 2) like 2 factor (Nrf2) on the development of atherosclerosis and liver injury in an obese, hypercholesterolemic mouse model. METHODS AND RESULTS: Two-month-old male low-density lipoprotein receptor-deficient mice were lethally irradiated and transplanted with either wild type or Nrf2-deficient (Nrf2(-/-)) bone marrow cells. At 3 months of age, mice were placed on an obesogenic high-fat diet (HFD), high-cholesterol diet for 7 months. Despite no differences in body weight, body fat percentage, liver fat, plasma glucose, lipids, or insulin, the HFD-fed Nrf2(-/-) bone marrow recipients had increased proinflammatory vascular gene expression, a significant increase in atherosclerosis area (18% versus 28%; P=0.018) and lesion complexity, and a marked increase in liver fibrosis. The acceleration of vascular and liver injury may arise from enhanced macrophage migration, inflammation, and oxidative stress resulting from myeloid Nrf2 deficiency. CONCLUSIONS: Myeloid-derived Nrf2 activity attenuates atherosclerosis development and liver inflammation and fibrosis associated with obesity. Prevention of oxidative stress in macrophage and other myeloid lineage cells may be an important therapeutic target to reduce inflammation-driven complications of obesity.


Assuntos
Aterosclerose/epidemiologia , Deleção de Genes , Hipercolesterolemia/complicações , Cirrose Hepática/epidemiologia , Células Mieloides/metabolismo , Fator 2 Relacionado a NF-E2/deficiência , Obesidade/complicações , Animais , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Transplante de Medula Óssea , Movimento Celular/fisiologia , Comorbidade , Modelos Animais de Doenças , Hipercolesterolemia/epidemiologia , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Obesidade/epidemiologia , Estresse Oxidativo/fisiologia , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores de LDL/metabolismo , Fatores de Risco
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