Novel formulation of a methotrexate derivative with a lipid nanoemulsion

Juliana A Moura1, Claudete J Valduga2, Elaine R Tavares1, Iara F Kretzer1,4, Durvanei A Maria3, Raul C Maranhão1,4 1Heart Institute of the Medical School Hospital, University of São Paulo; 2Bandeirante University of São Paulo; 3Butantan Institute, 4Facult...

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Autores principales: Moura JA, Valduga CJ, Tavares ER, Kretzer IF, Maria DA, Maranhao RC
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Publicado: Dove Medical Press 2011
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spelling oai:doaj.org-article:ea413c82c3e0414ca1e7ff2563812fa02021-12-02T07:11:22ZNovel formulation of a methotrexate derivative with a lipid nanoemulsion1176-91141178-2013https://doaj.org/article/ea413c82c3e0414ca1e7ff2563812fa02011-10-01T00:00:00Zhttp://www.dovepress.com/novel-formulation-of-a-methotrexate-derivative-with-a-lipid-nanoemulsi-a8453https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Juliana A Moura1, Claudete J Valduga2, Elaine R Tavares1, Iara F Kretzer1,4, Durvanei A Maria3, Raul C Maranhão1,4 1Heart Institute of the Medical School Hospital, University of São Paulo; 2Bandeirante University of São Paulo; 3Butantan Institute, 4Faculty of Pharmaceutical Sciences of the University of São Paulo, São Paulo, Brazil 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 [IC50] 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 (LD50 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. Keywords: nanoparticles, methotrexate, didodecyl methotrexate, drug delivery, cholesterolMoura JAValduga CJTavares ERKretzer IFMaria DAMaranhao RCDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2011, Iss default, Pp 2285-2295 (2011)
institution DOAJ
collection DOAJ
language EN
topic Medicine (General)
R5-920
spellingShingle Medicine (General)
R5-920
Moura JA
Valduga CJ
Tavares ER
Kretzer IF
Maria DA
Maranhao RC
Novel formulation of a methotrexate derivative with a lipid nanoemulsion
description Juliana A Moura1, Claudete J Valduga2, Elaine R Tavares1, Iara F Kretzer1,4, Durvanei A Maria3, Raul C Maranhão1,4 1Heart Institute of the Medical School Hospital, University of São Paulo; 2Bandeirante University of São Paulo; 3Butantan Institute, 4Faculty of Pharmaceutical Sciences of the University of São Paulo, São Paulo, Brazil 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 [IC50] 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 (LD50 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. Keywords: nanoparticles, methotrexate, didodecyl methotrexate, drug delivery, cholesterol
format article
author Moura JA
Valduga CJ
Tavares ER
Kretzer IF
Maria DA
Maranhao RC
author_facet Moura JA
Valduga CJ
Tavares ER
Kretzer IF
Maria DA
Maranhao RC
author_sort Moura JA
title Novel formulation of a methotrexate derivative with a lipid nanoemulsion
title_short Novel formulation of a methotrexate derivative with a lipid nanoemulsion
title_full Novel formulation of a methotrexate derivative with a lipid nanoemulsion
title_fullStr Novel formulation of a methotrexate derivative with a lipid nanoemulsion
title_full_unstemmed Novel formulation of a methotrexate derivative with a lipid nanoemulsion
title_sort novel formulation of a methotrexate derivative with a lipid nanoemulsion
publisher Dove Medical Press
publishDate 2011
url https://doaj.org/article/ea413c82c3e0414ca1e7ff2563812fa0
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