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1.
Clinics (Sao Paulo) ; 74: e989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31291391

RESUMO

OBJECTIVE: Rapidly dividing cells in multiple types of cancer and inflammatory diseases undergo high low density lipoprotein (LDL) uptake for membrane synthesis, and coupling an LDL-like nanoemulsion, containing lipid nanoparticles (LDE) to a chemotherapeutic agent efficiently targets these cells without significant systemic effects. This was a prospective exploratory study that evaluated the uptake of a radioactively labeled LDE emulsion by receptors of endometriotic foci and the capacity of the LDE for cellular internalization. METHODS: The lipid profile of each patient was determined before surgery, and labeled LDE were injected into fourteen patients with intestinal or nonintestinal endometriosis. The radioactivity of each tissue sample (intestinal endometriosis, nonintestinal endometriosis, healthy peritoneum, or topical endometrium) was measured. RESULTS: The group with intestinal endometriosis presented higher levels of plasma LDL but lower LDE uptake by foci than the nonintestinal group, suggesting less cell division and more fibrosis. The uptake of LDE was highest in the topical endometrium, followed by the healthy peritoneum, and lowest in the endometriotic lesion. Since the endometriotic foci showed significant LDE uptake, there was likely increased consumption of LDL by these cells, similar to cells in cancers and inflammatory diseases. Plasma cholesterol levels had no influence on LDE uptake, which showed that the direct delivery of the nanoemulsion to target tissues was independent of serum lipoproteins. There were no significant differences in the parameters (p>0.01) because of the small sample size, but the findings were similar to those of previous studies. CONCLUSION: Nanotechnology is a promising therapeutic option for surgery and hormonal blockage for deep endometriosis, with a lower complication rate and no systemic side effects.

2.
Vascul Pharmacol ; 115: 46-54, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30797043

RESUMO

Chemotherapeutic agents used in cancer treatment associated to nanoparticles (LDE) that mimic the composition of low-density lipoprotein and buffer their toxicity can have strong anti-atherosclerosis action, as we showed in cholesterol-fed rabbits. Here, a novel preparation of docetaxel (DTX) carried in LDE was evaluated. Eighteen rabbits were fed 1% cholesterol during 8 weeks. After the first 4 weeks, 9 animals were treated for 4 weeks with intravenous LDE-DTX (1 mg/kg/week) and 9 with LDE only (controls) once a week for 4 weeks. Animals were then euthanized and the aortas were analyzed for morphometry, immunohistochemistry and Western blot. LDE-DTX treated group showed 80% reduction of atheroma area compared to controls. LDE-DTX treatment reduced in 60% the protein expression of macrophage marker CD68 and of MCP-1 in 80%. LDE-DTX pronouncedly lowered expression of pro-inflammatory markers NF-κB, TNF-α, IL-1ß, IL-6 and von Willebrand factor and elicited 40% reduction in cell proliferation marker PCNA. The presence of smooth muscle cells in the intima was 85% smaller than in controls. Pro-apoptotic caspase 3, caspase 9, Bax, and anti-apoptotic Bcl-2 all were reduced by LDE-DTX. Protein expression of MMP-2 and MMP-9, TGF-ß, and collagen 1 and 3 were also markedly lowered by the LDE-DTX treatment. Animals showed no hematological, hepatic or renal toxicity consequent to LDE-DTX treatment. In conclusion, LDE-DTX showed a wide array of strong effects on pro-inflammatory and proliferation-promoting factors that drive the lesion development. These findings and the lack of observable toxicity indicate that LDE-DTX can be a candidate for future clinical trials.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Docetaxel/farmacologia , Lipídeos/química , Nanopartículas , Placa Aterosclerótica , Animais , Anti-Inflamatórios/química , Aorta/metabolismo , Aorta/patologia , Aortite/metabolismo , Aortite/patologia , Proteínas Reguladoras de Apoptose/metabolismo , Aterosclerose/metabolismo , Aterosclerose/patologia , Morte Celular/efeitos dos fármacos , Colesterol na Dieta , Dieta Hiperlipídica , Modelos Animais de Doenças , Docetaxel/química , Composição de Medicamentos , Colágenos Fibrilares/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fator de von Willebrand/metabolismo
3.
Clinics ; 74: e989, 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1011914

RESUMO

OBJECTIVE: Rapidly dividing cells in multiple types of cancer and inflammatory diseases undergo high low density lipoprotein (LDL) uptake for membrane synthesis, and coupling an LDL-like nanoemulsion, containing lipid nanoparticles (LDE) to a chemotherapeutic agent efficiently targets these cells without significant systemic effects. This was a prospective exploratory study that evaluated the uptake of a radioactively labeled LDE emulsion by receptors of endometriotic foci and the capacity of the LDE for cellular internalization. METHODS: The lipid profile of each patient was determined before surgery, and labeled LDE were injected into fourteen patients with intestinal or nonintestinal endometriosis. The radioactivity of each tissue sample (intestinal endometriosis, nonintestinal endometriosis, healthy peritoneum, or topical endometrium) was measured. RESULTS: The group with intestinal endometriosis presented higher levels of plasma LDL but lower LDE uptake by foci than the nonintestinal group, suggesting less cell division and more fibrosis. The uptake of LDE was highest in the topical endometrium, followed by the healthy peritoneum, and lowest in the endometriotic lesion. Since the endometriotic foci showed significant LDE uptake, there was likely increased consumption of LDL by these cells, similar to cells in cancers and inflammatory diseases. Plasma cholesterol levels had no influence on LDE uptake, which showed that the direct delivery of the nanoemulsion to target tissues was independent of serum lipoproteins. There were no significant differences in the parameters (p>0.01) because of the small sample size, but the findings were similar to those of previous studies. CONCLUSION: Nanotechnology is a promising therapeutic option for surgery and hormonal blockage for deep endometriosis, with a lower complication rate and no systemic side effects.

4.
Oxid Med Cell Longev ; 2018: 3967213, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29765495

RESUMO

Marfan syndrome (MFS) cardiovascular manifestations such as aortic aneurysms and cardiomyopathy carry substantial morbidity/mortality. We investigated the effects of lipoic acid, an antioxidant, on ROS production and aortic remodeling in a MFS mgΔloxPneo mouse model. MFS and WT (wild-type) 1-month-old mice were allocated to 3 groups: untreated, treated with losartan, and treated with lipoic acid. At 6 months old, echocardiography, ROS production, and morphological analysis of aortas were performed. Aortic ROS generation in 6-month-old MFS animals was higher at advanced stages of disease in MFS. An unprecedented finding in MFS mice analyzed by OCT was the occurrence of focal inhomogeneous regions in the aortic arch, either collagen-rich extremely thickened or collagen-poor hypotrophic regions. MFS animals treated with lipoic acid showed markedly reduced ROS production and lower ERK1/2 phosphorylation; meanwhile, aortic dilation and elastic fiber breakdown were unaltered. Of note, lipoic acid treatment associated with the absence of focal inhomogeneous regions in MFS animals. Losartan reduced aortic dilation and elastic fiber breakdown despite no change in ROS generation. In conclusion, oxidant generation by itself seems neutral with respect to aneurysm progression in MFS; however, lipoic acid-mediated reduction of inhomogeneous regions may potentially associate with less anisotropy and reduced chance of dissection/rupture.


Assuntos
Doenças da Aorta/tratamento farmacológico , Síndrome de Marfan/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Fenótipo
5.
J Cardiovasc Pharmacol Ther ; 23(6): 561-569, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29779420

RESUMO

In previous studies, it was demonstrated that lipid core nanoparticles (LDE) resemble the low-density lipoprotein structure and carrying the antiproliferative agent paclitaxel (PTX) strongly reduced atherosclerosis lesions induced in rabbits by cholesterol feeding. Currently, the aim was to verify whether combining LDE-PTX treatment with methotrexate (MTX) associated with LDE (LDE-MTX) could accelerate the atherosclerosis regression attained with single LDE-PTX treatment, after withdrawing the cholesterol feeding. Thirty-eight rabbits were fed 1% cholesterol chow for 8 weeks. Six of these rabbits were then euthanized for analyses of the aorta (controls). In the remaining rabbits, cholesterol feeding was withdrawn, and those 32 animals were allocated to 3 groups submitted to different 8-week intravenous treatments, all once/week: LDE-PTX (n = 10; 4 mg/kg), LDE-PTX + LDE-MTX (n = 11; 4 mg/kg), and LDE-alone (n = 11). Rabbits were then euthanized and aortas were excised for morphometric, immunohistochemical, and gene expression analyses. After cholesterol feeding withdrawal, in comparison with LDE-alone group, both LDE-PTX and LDE-PTX + LDE-MTX treatments had the ability to increase the regression of plaque areas: -49% in LDE-PTX and -59% for LDE-PTX + LDE-MTX. However, only LDE-PTX + LDE-MTX treatment elicited reduction in the intima area, estimated in -57%. Macrophage presence in aortic lesions was reduced 48% by LDE-PTX and 43% by LDE-PTX + LDE-MTX treatment. Matrix metalloproteinase 9 was reduced by either LDE-PTX (74%) or LDE-PTX + LDE-MTX (78%). Tumor necrosis factor α gene expression was reduced 65% by LDE-PTX and 79% by LDE-PTX + LDE-MTX. In conclusion, treatment with LDE-PTX indeed accelerated plaque reduction after cholesterol feeding; LDE-PTX + LDE-MTX further increased this effect, without any observed toxicity. These results pave the way for the use of combined chemotherapy to achieve stronger effects on aggravated, highly inflamed atherosclerotic lesions.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/tratamento farmacológico , Fármacos Cardiovasculares/administração & dosagem , Colesterol na Dieta , Lipídeos/química , Metotrexato/administração & dosagem , Nanopartículas , Paclitaxel/administração & dosagem , Placa Aterosclerótica , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/sangue , Doenças da Aorta/patologia , Aterosclerose/sangue , Aterosclerose/patologia , Fármacos Cardiovasculares/química , Citocinas/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Quimioterapia Combinada , Mediadores da Inflamação/metabolismo , Lipossomos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Metotrexato/química , Paclitaxel/química , Coelhos
6.
Lipids ; 53(2): 177-187, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29394450

RESUMO

Left ventricular (LV) remodeling after myocardial infarction constitutes the structural basis for ventricular dysfunction and heart failure. The characterization underlying the expression of lipoprotein receptors in cardiac dysfunction is scarcely explored. The aim of this study was to analyze the status of lipoprotein receptors on the infarcted and noninfarcted areas of LV and to verify whether nanoparticles that mimic the lipid structure of low-density lipoprotein (LDL) and have the ability to bind to LDL receptors (LDE) are taken up more avidly by the noninfarcted LV. 13 male Wistar rats with left coronary artery ligation (myocardial infarction [MI]) and 12 animals with SHAM operation (SHAM) were used in this study. 6 weeks after the procedure, the quantification of low-density lipoprotein receptor (LDLR), LDL receptor-related protein 1 (LRP1), scavenger receptor-class B type I (SR-BI) lipoprotein receptors, and PCNA proliferation marker, and tissue uptake of radioactively labeled LDE were performed. Immunohistochemistry and Western blot analysis showed that LDLR, LRP1, SR-BI, and PCNA, expression in infarcted area of MI was remarkably higher than SHAM and noninfarcted subendocardial (SEN) and interstitial (INT) areas. In addition, in SEN noninfarcted area of MI, the presence of LDLR was about threefold higher than in SHAM SEN and INT noninfarcted areas. The LDE uptake of noninfarcted LV of MI group was about 30% greater than that of SHAM group. In conclusion, these findings regarding the status of lipoprotein receptors after MI induction could help to establish mechanisms on myocardial repairing. In conclusion, infarcted rats with LV dysfunction showed increased expression of lipoprotein receptors mainly in the infarcted area.


Assuntos
Infarto do Miocárdio/genética , Receptores de Lipoproteínas/genética , Disfunção Ventricular Esquerda/genética , Animais , Perfilação da Expressão Gênica , Ketamina , Masculino , Infarto do Miocárdio/induzido quimicamente , Infarto do Miocárdio/metabolismo , Ratos , Ratos Wistar , Receptores de Lipoproteínas/metabolismo , Disfunção Ventricular Esquerda/induzido quimicamente , Disfunção Ventricular Esquerda/metabolismo , Xilazina
7.
Oxid Med Cell Longev ; 2017: 5343972, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28781721

RESUMO

Diabetic cardiomyopathy (DCM) is characterized by cardiac remodeling and impaired diastolic function that may lead to heart failure. The aim of this study was to evaluate oxidative stress, inflammatory cells, and fibrosis in both subendocardial (SEN) and interstitial (INT) areas of the myocardium. Male Wistar rats were allocated to 2 groups of 9 animals, a control (CT) group and streptozotocin-induced diabetes (DM). After 8 weeks, echocardiography morphometry, protein expression, and confocal microscopy in SEN and INT areas of the left ventricle (LV) were performed. The echocardiographic analysis showed that diabetes induction leads to cardiac dilation, hypertrophy, and LV diastolic dysfunction. As compared to CT, the induction of diabetes increased inflammatory cells and fibrosis in both SEN and INT areas of DM myocardium and increased ROS generation only in SEN. Comparing the SEN and INT areas in the DM group, inflammatory cells and fibrosis in SEN were greater than in INT. In conclusion, diabetic myocardium SEN area, wherein oxidative stress was more pronounced, is more susceptible to cardiac dysfunction than INT area. This finding can be important for the understanding of the heart remodeling process occurring in DCM and perhaps to engender targeted therapies to attenuate or revert DCM-related diastolic dysfunction.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Coração/fisiologia , Miocárdio/metabolismo , Estresse Oxidativo/fisiologia , Animais , Western Blotting , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Cardiomiopatias Diabéticas/imunologia , Ecocardiografia , Masculino , Miocárdio/imunologia , Miocárdio/patologia , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Disfunção Ventricular Esquerda/imunologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
8.
Int J Nanomedicine ; 12: 3767-3784, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28553113

RESUMO

PURPOSE: Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment. MATERIALS AND METHODS: Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. RESULTS: LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. CONCLUSION: The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials.


Assuntos
Lipídeos/química , Metotrexato/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Vasos Coronários/cirurgia , Lipídeos/farmacologia , Masculino , Metotrexato/farmacologia , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Nanopartículas/química , Necrose/tratamento farmacológico , Necrose/patologia , Ratos Wistar , Fator A de Crescimento do Endotélio Vascular/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
9.
Ann Thorac Surg ; 104(2): 577-583, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28347533

RESUMO

BACKGROUND: Coronary allograft vasculopathy is an inflammatory-proliferative process that compromises the long-term success of heart transplantation and currently has no effective prevention and treatment. Lipid nanoparticles, termed LDE can carry chemotherapeutic agents in the circulation and concentrates them in the heart. METHODS: Twenty-eight rabbits fed a cholesterol-rich diet and submitted to heterotopic heart transplantation were treated with cyclosporine A (10 mg/kg daily) and allocated to four groups of 7 animals treated with intravenous LDE-methotrexate (MTX; 4 mg/kg weekly), with LDE-paclitaxel (PACLI; 4 mg/kg weekly), or with LDE-PACLI (4 mg/kg weekly) and LDE-MTX (4 mg/kg weekly). A control group was treated with only weekly intravenous saline solution. Animals were euthanized 6 weeks later for morphometric, histologic, immunohistochemical, and gene expression analysis of the graft and native hearts. RESULTS: Compared with controls, grafts of rabbits treated with LDE-PACLI showed 50% reduction of coronary stenosis, and in the LDE-MTX and LDE-MTX/PACLI stenosis was approximately 18% less than in control, but this difference was not statistically significant. In the three treatment groups, macrophage infiltration was decreased. In the LDE-MTX group, gene expression of proinflammatory factors tumor necrosis factor-α, monocyte chemoattractant protein 1, interleukin 18, vascular cellular adhesion molecule 1, and matrix metalloproteinase 12 was strongly diminished, whereas expression of antiinflammatory interleukin 10 increased. In the LDE-PACLI and LDE-PACLI/MTX groups, proinflammatory and antiinflammatory gene expressions were not consistently changed by the treatments. CONCLUSIONS: LDE-PACLI promoted strong improvement of cardiac allograft vasculopathy, but the decrease in coronary stenosis by LDE-MTX and LDE-MTX/PACLI was not significant. All three treatments decreased macrophage infiltration in the graft. These results may encourage future clinical trials to test this new therapeutic approach to coronary allograft vasculopathy.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Portadores de Fármacos , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Metotrexato/farmacocinética , Nanopartículas/administração & dosagem , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Doença da Artéria Coronariana/etiologia , Citocinas/biossíntese , Citocinas/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Rejeição de Enxerto/genética , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto/efeitos dos fármacos , Imuno-Histoquímica , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Injeções Intravenosas , Metotrexato/administração & dosagem , Miocárdio/metabolismo , Paclitaxel/administração & dosagem , RNA/genética , Coelhos , Reação em Cadeia da Polimerase em Tempo Real
10.
Hum Reprod ; 32(2): 332-339, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27986818

RESUMO

STUDY QUESTION: Is mRNA expression of LDL receptors altered in deep bowel endometriotic foci? SUMMARY ANSWER: mRNA expression of LDL receptors is up-regulated in deep bowel endometriotic foci of patients with endometriosis. WHAT IS KNOWN ALREADY: Several studies have demonstrated the overexpression of low-density lipoprotein receptors in various tumour cell lines and endometriosis has similar aspects to cancer, mainly concerning the pathogenesis of both diseases. This is the first study we know of to investigate lipoprotein receptors expression in deep endometriosis with bowel involvement. STUDY DESIGN, SIZE, DURATION: During 2014-2015, an exploratory case-control study was conducted with 39 patients, including 20 women with a histological diagnosis of deep endometriosis compromising the bowel and 19 women without endometriosis who underwent laparoscopic tubal ligation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Peripheral blood samples were collected on the day of surgery for lipid profile analysis, and samples of endometrial tissue and of bowel endometriotic lesions were also collected. The tissue samples were sent for histopathological analysis and for LDL-R and LRP-1 gene expression screening using quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Patients with deep endometriosis had lower LDL-cholesterol than patients without the disease (119 ± 23 versus 156 ± 35; P = 0.001). Gene expression analysis of LDL receptors revealed that LDL-R was more highly expressed in endometriotic lesions when compared to the endometrium of the same patient but not more than in the endometrium of women without endometriosis (0.027 ± 0.022 versus 0.012 ± 0.009 versus 0.019 ± 0.01, respectively; P < 0.001). LRP-1 was more highly expressed in endometriotic lesions, both when compared with the endometrium of the same patient and when compared with the endometrium of patients without the disease (0.307 ± 0.207 versus 0.089 ± 0.076 and versus 0.126 ± 0.072, respectively; P < 0.001). The study also showed that LDL-R gene expression in the endometrium of women with endometriosis was higher during the secretory phase of the menstrual cycle (P = 0.001). LRP-1 gene expression was increased during the secretory phase in the endometrium of women without the disease (P = 0.008). LIMITATIONS, REASONS FOR CAUTION: In the endometriotic lesions, the presence of fibrosis is substantial, restricting access to the stromal and glandular components of the lesion. Despite that, we found that LDL receptor mRNA was overexpressed. Future studies may perform laser microdissection to isolate the area of interest in the target tissue, excluding fibrosis contamination. WIDER IMPLICATIONS OF THE FINDINGS: This study supports the feasibility of LDL-R targeted therapy in the treatment of deep endometriosis. STUDY FUNDING/COMPETING INTERESTS: This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP #2011/17245-0). The authors have no conflicts of interest to declare.


Assuntos
Endometriose/metabolismo , Enteropatias/metabolismo , Mucosa Intestinal/metabolismo , Receptores de LDL/metabolismo , Adulto , Estudos de Casos e Controles , Endometriose/genética , Endometriose/patologia , Feminino , Humanos , Enteropatias/genética , Enteropatias/patologia , Intestinos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/genética , Regulação para Cima
11.
Clinics (Sao Paulo) ; 71(1): 54-8, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26872084

RESUMO

OBJECTIVE: To test the hypothesis that intravenous use of methotrexate associated with lipid nanoemulsions can achieve superior anti-inflammatory effects in the joints of rabbits with antigen-induced arthritis compared with commercial methotrexate. METHODS: Arthritis was induced in New Zealand rabbits sensitized with methylated bovine serum albumin and subsequently intra-articularly injected with the antigen. A nanoemulsion of methotrexate labeled with 3H-cholesteryl ether (4 mg/kg methotrexate) was then intravenously injected into four rabbits to determine the plasma decaying curves and the biodistribution of the methotrexate nanoemulsion by radioactive counting. Additionally, the pharmacokinetics of the methotrexate nanoemulsion were determined by high-pressure liquid chromatography. Twenty-four hours after arthritis induction, the animals were allocated into three groups, with intravenous injection with saline solution (n=9), methotrexate nanoemulsion (0.5 µmol/kg methotrexate, n=7), or commercial methotrexate (0.5 µmol/kg, n=4). The rabbits were sacrificed 24 h afterward. Synovial fluid was then collected for protein leakage and cell content analyses and synovial membranes were collected for histopathological analysis. RESULTS: The methotrexate nanoemulsion was taken up mainly by the liver and the uptake by arthritic joints was two-fold greater than that by control joints. The methotrexate nanoemulsion treatment reduced leukocyte influx into the synovial fluid by nearly 65%; in particular, mononuclear and polymorphonuclear cells were reduced by 47 and 72%, respectively. In contrast, cell influx was unaffected following treatment with commercial methotrexate. Protein leakage into the arthritic knees of the rabbits was also more limited following methotrexate nanoemulsion treatment than following commercial methotrexate treatment. CONCLUSIONS: The intravenous methotrexate nanoemulsion showed anti-inflammatory effects on the synovia of arthritic joints that were clearly superior to the effects of a commercial methotrexate preparation. This result is conceivably due to greater methotrexate uptake by the joints when the drug is associated with a nanoemulsion.


Assuntos
Anti-Inflamatórios/farmacocinética , Artrite Experimental/metabolismo , Metotrexato/farmacocinética , Neutrófilos/efeitos dos fármacos , Animais , Anti-Inflamatórios/administração & dosagem , Artrite Experimental/sangue , Modelos Animais de Doenças , Injeções Intra-Articulares , Articulações/patologia , Contagem de Leucócitos , Metotrexato/administração & dosagem , Nanopartículas/metabolismo , Coelhos , Líquido Sinovial/citologia , Líquido Sinovial/metabolismo , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia
12.
Cardiovasc Drugs Ther ; 29(1): 15-22, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25672520

RESUMO

PURPOSE: Treatment of atherosclerotic rabbits with intravenous methotrexate or etoposide carried in lipid nanoemulsions (LDE) markedly reduced the lesions in the aorta. Here, the combined treatment with LDE-methotrexate and LDE-etoposide was investigated aiming to increase the anti-atherosclerosis effect. METHODS: Thirty-six male rabbits received a diet with 1 % cholesterol for 2 months. After the first month, the animals received 4 weekly intravenous injections of LDE-methotrexate (4 mg/kg dose), LDE-etoposide (6 mg/kg), or a combination of those two drugs, while the control animals were injected with LDE (n = 9 for each group). RESULTS: LDE-methotrexate+LDE-etoposide reduced aortic lesion areas by 95 % compared with controls and the intima-media ratio was reduced five-fold, whereas LDE-methotrexate reduced the lesions by 81 % and LDE-etoposide by 83 %. Compared to controls, the positive area of macrophages and MMP-9 in the arterial intima was significantly reduced in all treated groups (p < 0.001), but the MMP9 reduction was greater with the combined chemotherapy than the reduction achieved by the isolated treatments. Presence of CD3 positive cells was equal in controls and LDE-methotrexate+LDE-etoposide treated animals. However, FOXP3 positive T lymphocytes in the intima were increased in the LDE-methotrexate+LDE-etoposide rabbits. Weight, food intake evolution and the hematologic parameters suggested that the treatment had very low toxicity. CONCLUSIONS: Compared to the single treatments with LDE-methotrexate and LDE-etoposide, the combined treatment was more effective in reducing the atherosclerotic lesions. Because the toxicity of the novel drug-target combined scheme was low, those results favor the possibility of future clinical studies in patients with cardiovascular disease.


Assuntos
Aterosclerose/tratamento farmacológico , Etoposídeo/administração & dosagem , Lipídeos/administração & dosagem , Metotrexato/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/patologia , Aterosclerose/patologia , Quimioterapia Combinada , Emulsões , Etoposídeo/uso terapêutico , Lipídeos/química , Masculino , Metotrexato/uso terapêutico , Nanoestruturas/química , Coelhos
13.
Expert Opin Drug Deliv ; 12(7): 1135-47, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25585820

RESUMO

INTRODUCTION: Apart from statins, anti-platelet agents and invasive procedures, the anti-atherosclerotic medical weaponry for coronary heart disease (CHD) is scarce and only partially protects CHD patients from major adverse cardiac events. AREAS COVERED: Several novel non-invasive strategies are being developed to widen the therapeutic options. Among them, drug delivery tools were tested in vivo encompassing liposomes, micelles, polymeric, metallic and lipid nanoparticles used as carriers of statins, corticosteroids, a bisphosphonate, a glitazone, anti-cancer agents, a mycotoxin, a calcium channel blocker and a compound of traditional Chinese medicine. All preparations improved parameters related to atherosclerotic lesions induced in rabbits, rats and mice and reduced neointima formation in experiments aiming to prevent post-stenting restenosis. In subjects submitted to percutaneous coronary intervention, nanoparticle formulations of paclitaxel and alendronate showed safety but are still not conclusive regarding in-stent late loss. The experience of our group in atherosclerotic rabbits treated with non-protein lipid nanoparticles associated with anti-cancer drugs such as paclitaxel, etoposide and methotrexate is summarized, and preliminary safety data in CHD patients are anticipated. EXPERT OPINION: Taken together, these studies show that non-invasive drug-delivery systems may become promising tools to rescue CHD patients from the risks of severe and life-threatening lesions that should be more energetically treated.


Assuntos
Aterosclerose/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Nanopartículas , Animais , Antineoplásicos/administração & dosagem , Humanos , Lipossomos , Camundongos , Paclitaxel/administração & dosagem , Intervenção Coronária Percutânea/métodos , Coelhos , Ratos , Stents
14.
Int J Nanomedicine ; 8: 443-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23439784

RESUMO

OBJECTIVE: Commercial methotrexate formulations (MTX) have poor anti-inflammatory action for intra-articular treatment of rheumatoid arthritis. Our aim was to investigate whether an association between methotrexate and lipidic nanoemulsions (LDE) could improve MTX intra-articular action. METHODS: For its association to LDE, MTX was previously esterified with dodecyl bromide. LDE-MTX was prepared by high pressure homogenization. Antigen-induced arthritis (AIA) was achieved in rabbits sensitized with methylated bovine serum albumin, and the rabbits were subsequently intra-articularly injected with the antigen. Twenty-four hours after AIA induction, groups of four to nine rabbits were intra-articularly injected with increasing doses (0.0625-0.5 µmol/kg) of LDE-MTX, and were compared to treatment with 0.5 µmol/kg commercial MTX, LDE alone, and saline (controls). Synovial fluid was collected 48 hours after AIA induction for analysis of protein leakage and cell content. Synovial membranes were collected for histopathology. Uptake of LDE labeled with (3)H-cholesteryl ether by the synovial tissue was also determined. RESULTS: Uptake of radioactive LDE by arthritic joints was 2.5-fold greater than by normal joints. Treatment with intra-articular LDE-MTX elicited a clear dose response pattern by reducing the synovial leukocyte infiltrate (P = 0.004) and protein leakage (P = 0.032) when compared with arthritic non-treated joints. In contrast, the intra-articular injection of commercial MTX and LDE did not reduce leukocyte infiltrate or protein leakage. Toxicity to treatment was not observed in any of the animals. CONCLUSION: The association between LDE and MTX presented a marked anti-inflammatory effect that was absent after intra-articular commercial MTX treatment. Therefore, the new formulation is a candidate for future clinical studies.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Lipídeos/administração & dosagem , Lipídeos/farmacocinética , Metotrexato/administração & dosagem , Análise de Variância , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/metabolismo , Citocinas/metabolismo , Emulsões/administração & dosagem , Emulsões/química , Emulsões/farmacocinética , Injeções Intra-Articulares , Lipídeos/química , Metotrexato/química , Metotrexato/farmacocinética , Infiltração de Neutrófilos/efeitos dos fármacos , Coelhos , Líquido Sinovial/química , Líquido Sinovial/citologia , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo
15.
Int J Nanomedicine ; 6: 2285-95, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22072866

RESUMO

BACKGROUND: Lipid nanoemulsions that bind to low-density lipoprotein receptors can concentrate chemotherapeutic agents in tissues with low-density lipoprotein receptor overexpression and decrease the toxicity of the treatment. The aim of this study was to develop a new formulation using a lipophilic derivative of methotrexate, ie, didodecyl methotrexate (ddMTX), associated with a lipid nanoemulsion (ddMTX-LDE). METHODS: ddMTX was synthesized by an esterification reaction between methotrexate and dodecyl bromide. The lipid nanoemulsion was prepared by four hours of ultrasonication of a mixture of phosphatidylcholine, triolein, and cholesteryloleate. Association of ddMTX with the lipid nanoemulsion was performed by additional cosonication of ddMTX with the previously prepared lipid nanoemulsion. Formulation stability was evaluated, and cell uptake, cytotoxicity, and acute animal toxicity studies were performed. RESULTS: The yield of ddMTX incorporation was 98% and the particle size of LDE-ddMTX was 60 nm. After 48 hours of incubation with plasma, approximately 28% ddMTX was released from the lipid nanoemulsion. The formulation remained stable for at least 45 days at 4°C. Cytotoxicity of LDE-ddMTX against K562 and HL60 neoplastic cells was higher than for methotrexate (50% inhibitory concentration [IC(50)] 1.6 versus 18.2 mM and 0.2 versus 26 mM, respectively), and cellular uptake of LDE-ddMTX was 90-fold higher than that of methotrexate in K562 cells and 75-fold in HL60 cells. Toxicity of LDE-ddMTX, administered at escalating doses, was higher than for methotrexate (LD(50) 115 mg/kg versus 470 mg/kg; maximum tolerated dose 47 mg/kg versus 94 mg/kg) in mice. However, the hematological toxicity of LDE-ddMTX was lower than for methotrexate. CONCLUSION: LDE-ddMTX was stable, and uptake of the formulation by neoplastic cells was remarkably greater than of methotrexate, which resulted in markedly greater cytotoxicity. LDE-ddMTX is thus a promising formulation to be tested in future animal models of cancer or rheumatic disease, wherein methotrexate is widely used.


Assuntos
Lipídeos/administração & dosagem , Lipídeos/química , Metotrexato/administração & dosagem , Metotrexato/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Contagem de Células Sanguíneas , Sistemas de Liberação de Medicamentos , Emulsões/administração & dosagem , Emulsões/química , Feminino , Células HL-60 , Humanos , Células K562 , Estimativa de Kaplan-Meier , Dose Máxima Tolerável , Metotrexato/farmacocinética , Camundongos , Camundongos Endogâmicos BALB C , Testes de Toxicidade
16.
Int J Nanomedicine ; 6: 2297-304, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-22072867

RESUMO

OBJECTIVES: Cholesterol-rich nanoemulsions (LDE) bind to low-density lipoprotein (LDL) receptors and after injection into the bloodstream concentrate in aortas of atherosclerotic rabbits. Association of paclitaxel with LDE markedly reduces the lesions. In previous studies, treatment of refractory cancer patients with etoposide associated with LDE had been shown devoid of toxicity. In this study, the ability of etoposide to reduce lesions and inflammatory factors in atherosclerotic rabbits was investigated. METHODS: Eighteen New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, nine animals were treated with four weekly intravenous injections of etoposide oleate (6 mg/kg) associated with LDE, and nine control animals were treated with saline solution injections. RESULTS: LDE-etoposide reduced the lesion areas of cholesterol-fed animals by 85% and intima width by 50% and impaired macrophage and smooth muscle cell invasion of the intima. Treatment also markedly reduced the protein expression of lipoprotein receptors (LDL receptor, LDL-related protein-1, cluster of differentiation 36, and scavenger receptor class B member 1), inflammatory cytokines (interleukin-1ß and tumor necrosis factor-α), matrix metallopeptidase-9, and cell proliferation markers (topoisomerase IIα and tubulin). CONCLUSION: The ability of LDE-etoposide to strongly reduce the lesion area and the inflammatory process warrants the great therapeutic potential of this novel preparation to target the inflammatory-proliferative basic mechanisms of the disease.


Assuntos
Aterosclerose/tratamento farmacológico , Colesterol/administração & dosagem , Etoposídeo/farmacologia , Nanoestruturas/administração & dosagem , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Ingestão de Alimentos/efeitos dos fármacos , Emulsões/administração & dosagem , Emulsões/farmacologia , Emulsões/toxicidade , Eritrócitos/efeitos dos fármacos , Etoposídeo/toxicidade , Histocitoquímica , Leucócitos/efeitos dos fármacos , Lipoproteínas/sangue , Masculino , Nanoestruturas/toxicidade , Coelhos , Receptores de LDL/sangue , Testes de Toxicidade
17.
J Thorac Cardiovasc Surg ; 141(6): 1522-8, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21458008

RESUMO

OBJECTIVE: In previous studies cholesterol-rich nanoemulsions (LDE) resembling low-density lipoprotein were shown to concentrate in atherosclerotic lesions of rabbits. Lesions were pronouncedly reduced by treatment with paclitaxel associated with LDE. This study aimed to test the hypothesis of whether LDE-paclitaxel is able to concentrate in grafted hearts of rabbits and to ameliorate coronary allograft vasculopathy after the transplantation procedure. METHODS: Twenty-one New Zealand rabbits fed 0.5% cholesterol were submitted to heterotopic heart transplantation at the cervical position. All rabbits undergoing transplantation were treated with cyclosporin A (10 mg · kg(-1) · d(-1) by mouth). Eleven rabbits were treated with LDE-paclitaxel (4 mg/kg body weight paclitaxel per week administered intravenously for 6 weeks), and 10 control rabbits were treated with 3 mL/wk intravenous saline. Four control animals were injected with LDE labeled with [(14)C]-cholesteryl oleate ether to determine tissue uptake. RESULTS: Radioactive LDE uptake by grafts was 4-fold that of native hearts. In both groups the coronary arteries of native hearts showed no stenosis, but treatment with LDE-paclitaxel reduced the degree of stenosis in grafted hearts by 50%. The arterial luminal area in grafts of the treated group was 3-fold larger than in control animals. LDE-paclitaxel treatment resulted in a 7-fold reduction of macrophage infiltration. In grafted hearts LDE-paclitaxel treatment reduced the width of the intimal layer and inhibited the destruction of the medial layer. No toxicity was observed in rabbits receiving LDE-paclitaxel treatment. CONCLUSIONS: LDE-paclitaxel improved posttransplantation injury to the grafted heart. The novel therapeutic approach for heart transplantation management validated here is thus a promising strategy to be explored in future clinical studies.


Assuntos
Fármacos Cardiovasculares/administração & dosagem , Estenose Coronária/prevenção & controle , Portadores de Fármacos , Emulsões , Transplante de Coração/efeitos adversos , Nanopartículas , Paclitaxel/administração & dosagem , Paclitaxel/química , Análise de Variância , Animais , Fármacos Cardiovasculares/química , Estenose Coronária/sangue , Estenose Coronária/etiologia , Estenose Coronária/patologia , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Masculino , Miocárdio/patologia , Coelhos , Índice de Gravidade de Doença , Fatores de Tempo
18.
Atherosclerosis ; 197(2): 959-66, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18289548

RESUMO

A cholesterol-rich nanoemulsion (LDE) that resembles LDL binds to the LDL receptors and after injection into the blood stream may concentrate in cells with LDL receptor overexpression, as occurs in neoplasias and other proliferative processes. Thus, LDE can be used as vehicle to target drugs against those cells. The current study was designed to verify in rabbits whether LDE concentrates in the lesioned rabbit artery and whether a paclitaxel derivative, paclitaxel oleate, associated to LDE could reduce the atherosclerotic lesions. Sixteen male New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30 under cholesterol feeding, eight animals were treated with four weekly intravenous injections of LDE-paclitaxel (4 mg/kg) and eight with four weekly intravenous saline solution injections for additional 30 days. On day 60, the animals were sacrificed for analysis. The uptake of LDE labeled with [(14)C]-cholesteryl oleate by the aortic arch of cholesterol-fed rabbits was twice as much that observed in animals fed only regular chow. LDE-paclitaxel reduced the lesion areas of cholesterol-fed animals by 60% and intima-media ratio fourfold and inhibited the macrophage migration and the smooth muscle cell proliferation and invasion of the intima. LDE-paclitaxel treatment had no toxicity. In conclusion, LDE-paclitaxel produced pronounced atherosclerosis regression without toxicity and has shown remarkable potential in cardiovascular therapeutics.


Assuntos
Anticolesterolemiantes/farmacologia , Aterosclerose/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Paclitaxel/farmacologia , Animais , Anticolesterolemiantes/administração & dosagem , Aorta Torácica/efeitos dos fármacos , Colesterol/administração & dosagem , Modelos Animais de Doenças , Emulsões/administração & dosagem , Masculino , Paclitaxel/administração & dosagem , Coelhos
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