Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model
Antônio Luiz Boechat,1,2,* Catiúscia Padilha de Oliveira,3,* Andrea Monteiro Tarragô,2 Allyson Guimarães da Costa,2 Adriana Malheiro,1,2 Silvia Stanisçuaski Guterres,3 Adriana Raffin Pohlmann3,41Departamento de Parasitologia, Instituto de Ci&e...
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2015
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oai:doaj.org-article:5d99923ef72740b7b27c0e55b60059102021-12-02T02:13:09ZMethotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model1178-2013https://doaj.org/article/5d99923ef72740b7b27c0e55b60059102015-10-01T00:00:00Zhttps://www.dovepress.com/methotrexate-loaded-lipid-core-nanocapsules-are-highly-effective-in-th-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Antônio Luiz Boechat,1,2,* Catiúscia Padilha de Oliveira,3,* Andrea Monteiro Tarragô,2 Allyson Guimarães da Costa,2 Adriana Malheiro,1,2 Silvia Stanisçuaski Guterres,3 Adriana Raffin Pohlmann3,41Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, 2Programa de Pós-Graduação e Imunologia Básica e Aplicada, Universidade Federal do Amazonas, Manaus, 3Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, 4Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil*These authors contributed equally to this workBackground: Rheumatoid arthritis (RA) is the most common autoimmune disease in the word, affecting 1% of the population. Long-term prognosis in RA was greatly improved following the introduction of highly effective medications such as methotrexate (MTX). Despite the importance of this drug in RA, 8%–16% of patients must discontinue the treatment because of adverse effects. Last decade, we developed a promising new nanocarrier as a drug-delivery system, lipid-core nanocapsules.Objective: The aim of the investigation reported here was to evaluate if methotrexate-loaded lipid-core nanocapsules (MTX-LNC) reduce proinflammatory and T-cell-derived cytokines in activated mononuclear cells derived from RA patients and even in functional MTX-resistant conditions. We also aimed to find out if MTX-LNC would reduce inflammation in experimentally inflammatory arthritis at lower doses than MTX solution.Methods: Formulations were prepared by self-assembling methodology. The adjuvant arthritis was induced in Lewis rats (AIA) and the effect on edema formation, TNF-a levels, and interleukin-1 beta levels after treatment was evaluated. Mononuclear cells obtained from the synovial fluid of RA patients during articular infiltration procedures were treated with MTX solution and MTX-LNC. For in vitro experiments, the same dose of MTX was used in comparing MTX and MTX-LNC, while the dose of MTX in the MTX-LNC was 75% lower than the drug in solution in in vivo experiments.Results: Formulations presented nanometric and unimodal size distribution profiles, with D[4.3] of 175±17 nm and span of 1.6±0.2. Experimental results showed that MTX-LNC had the same effect as MTX on arthritis inhibition on day 28 of the experiment (P<0.0001); however, this effect was achieved earlier, on day 21 (P<0.0001), by MTX-LNC, and this formulation had reduced both TNF-α (P=0.001) and IL-1α (P=0.0002) serum levels by the last day of the experiment. Further, the MTX-LNC were more effective at reducing the cytokine production from mononuclear synovial cells than MTX.Conclusion: The MTX-LNC were better than the MTX solution at reducing proinflammatory cytokines and T-cell-derived cytokines such as interferon-gamma and interleukin-17A. This result, combined with the reduction in the dose required for therapy, shows that MTX-LNC are a very promising system for the treatment of RA.Keywords: drug delivery, drug targeting, arthritis, cytokines, TNF-α, IL-6, IL-1, IL-17A, IFN-γBoechat ALOliveira CPTarragô AMCosta AGMalheiro AGuterres SSPohlmann ARDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2015, Iss default, Pp 6603-6614 (2015) |
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Medicine (General) R5-920 Boechat AL Oliveira CP Tarragô AM Costa AG Malheiro A Guterres SS Pohlmann AR Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
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Antônio Luiz Boechat,1,2,* Catiúscia Padilha de Oliveira,3,* Andrea Monteiro Tarragô,2 Allyson Guimarães da Costa,2 Adriana Malheiro,1,2 Silvia Stanisçuaski Guterres,3 Adriana Raffin Pohlmann3,41Departamento de Parasitologia, Instituto de Ciências Biológicas, Universidade Federal do Amazonas, Manaus, 2Programa de Pós-Graduação e Imunologia Básica e Aplicada, Universidade Federal do Amazonas, Manaus, 3Programa de Pós-Graduação em Ciências Farmacêuticas, Faculdade de Farmácia, 4Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil*These authors contributed equally to this workBackground: Rheumatoid arthritis (RA) is the most common autoimmune disease in the word, affecting 1% of the population. Long-term prognosis in RA was greatly improved following the introduction of highly effective medications such as methotrexate (MTX). Despite the importance of this drug in RA, 8%–16% of patients must discontinue the treatment because of adverse effects. Last decade, we developed a promising new nanocarrier as a drug-delivery system, lipid-core nanocapsules.Objective: The aim of the investigation reported here was to evaluate if methotrexate-loaded lipid-core nanocapsules (MTX-LNC) reduce proinflammatory and T-cell-derived cytokines in activated mononuclear cells derived from RA patients and even in functional MTX-resistant conditions. We also aimed to find out if MTX-LNC would reduce inflammation in experimentally inflammatory arthritis at lower doses than MTX solution.Methods: Formulations were prepared by self-assembling methodology. The adjuvant arthritis was induced in Lewis rats (AIA) and the effect on edema formation, TNF-a levels, and interleukin-1 beta levels after treatment was evaluated. Mononuclear cells obtained from the synovial fluid of RA patients during articular infiltration procedures were treated with MTX solution and MTX-LNC. For in vitro experiments, the same dose of MTX was used in comparing MTX and MTX-LNC, while the dose of MTX in the MTX-LNC was 75% lower than the drug in solution in in vivo experiments.Results: Formulations presented nanometric and unimodal size distribution profiles, with D[4.3] of 175±17 nm and span of 1.6±0.2. Experimental results showed that MTX-LNC had the same effect as MTX on arthritis inhibition on day 28 of the experiment (P<0.0001); however, this effect was achieved earlier, on day 21 (P<0.0001), by MTX-LNC, and this formulation had reduced both TNF-α (P=0.001) and IL-1α (P=0.0002) serum levels by the last day of the experiment. Further, the MTX-LNC were more effective at reducing the cytokine production from mononuclear synovial cells than MTX.Conclusion: The MTX-LNC were better than the MTX solution at reducing proinflammatory cytokines and T-cell-derived cytokines such as interferon-gamma and interleukin-17A. This result, combined with the reduction in the dose required for therapy, shows that MTX-LNC are a very promising system for the treatment of RA.Keywords: drug delivery, drug targeting, arthritis, cytokines, TNF-α, IL-6, IL-1, IL-17A, IFN-γ |
| format |
article |
| author |
Boechat AL Oliveira CP Tarragô AM Costa AG Malheiro A Guterres SS Pohlmann AR |
| author_facet |
Boechat AL Oliveira CP Tarragô AM Costa AG Malheiro A Guterres SS Pohlmann AR |
| author_sort |
Boechat AL |
| title |
Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
| title_short |
Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
| title_full |
Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
| title_fullStr |
Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
| title_full_unstemmed |
Methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
| title_sort |
methotrexate-loaded lipid-core nanocapsules are highly effective in the control of inflammation in synovial cells and a chronic arthritis model |
| publisher |
Dove Medical Press |
| publishDate |
2015 |
| url |
https://doaj.org/article/5d99923ef72740b7b27c0e55b6005910 |
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