Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

Anna A Alekseeva,1 Ekaterina V Moiseeva,1 Natalia R Onishchenko,1 Ivan A Boldyrev,1 Alexander S Singin,2,&dagger; Andrey P Budko,2 Zoya S Shprakh,2 Julian G Molotkovsky,1 Elena L Vodovozova1 1M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Scienc...

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Autores principales:	Alekseeva AA, Moiseeva EV, Onishchenko NR, Boldyrev IA, Singin AS, Budko AP, Shprakh ZS, Molotkovsky JG, Vodovozova EL
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2017
Materias:	liposomes methotrexate lipophilic prodrug endocytosis hematological malignancies leukemia/lymphoma Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/35d451080f024fab83112a996cf37289
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spelling	oai:doaj.org-article:35d451080f024fab83112a996cf372892021-12-02T04:14:42ZLiposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma1178-2013https://doaj.org/article/35d451080f024fab83112a996cf372892017-05-01T00:00:00Zhttps://www.dovepress.com/liposomal-formulation-of-a-methotrexate-lipophilic-prodrug-assessment--peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Anna A Alekseeva,1 Ekaterina V Moiseeva,1 Natalia R Onishchenko,1 Ivan A Boldyrev,1 Alexander S Singin,2,&dagger; Andrey P Budko,2 Zoya S Shprakh,2 Julian G Molotkovsky,1 Elena L Vodovozova1 1M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 2N.N. Blokhin Russian Cancer Research Center, the Ministry of Health of the Russian Federation, Moscow, Russian Federation &dagger;Alexander S Singin passed away on October 4, 2011 Abstract: In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX-DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5–2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX. Keywords: liposomes, methotrexate, lipophilic prodrug, endocytosis, hematological malignancies, leukemia/lymphomaAlekseeva AAMoiseeva EVOnishchenko NRBoldyrev IASingin ASBudko APShprakh ZSMolotkovsky JGVodovozova ELDove Medical Pressarticleliposomesmethotrexatelipophilic prodrugendocytosishematological malignanciesleukemia/lymphomaMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 12, Pp 3735-3749 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	liposomes methotrexate lipophilic prodrug endocytosis hematological malignancies leukemia/lymphoma Medicine (General) R5-920
spellingShingle	liposomes methotrexate lipophilic prodrug endocytosis hematological malignancies leukemia/lymphoma Medicine (General) R5-920 Alekseeva AA Moiseeva EV Onishchenko NR Boldyrev IA Singin AS Budko AP Shprakh ZS Molotkovsky JG Vodovozova EL Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma
description	Anna A Alekseeva,1 Ekaterina V Moiseeva,1 Natalia R Onishchenko,1 Ivan A Boldyrev,1 Alexander S Singin,2,&dagger; Andrey P Budko,2 Zoya S Shprakh,2 Julian G Molotkovsky,1 Elena L Vodovozova1 1M.M. Shemyakin and Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, 2N.N. Blokhin Russian Cancer Research Center, the Ministry of Health of the Russian Federation, Moscow, Russian Federation &dagger;Alexander S Singin passed away on October 4, 2011 Abstract: In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX-DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5–2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX. Keywords: liposomes, methotrexate, lipophilic prodrug, endocytosis, hematological malignancies, leukemia/lymphoma
format	article
author	Alekseeva AA Moiseeva EV Onishchenko NR Boldyrev IA Singin AS Budko AP Shprakh ZS Molotkovsky JG Vodovozova EL
author_facet	Alekseeva AA Moiseeva EV Onishchenko NR Boldyrev IA Singin AS Budko AP Shprakh ZS Molotkovsky JG Vodovozova EL
author_sort	Alekseeva AA
title	Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma
title_short	Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma
title_full	Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma
title_fullStr	Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma
title_full_unstemmed	Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma
title_sort	liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse t-cell leukemic lymphoma
publisher	Dove Medical Press
publishDate	2017
url	https://doaj.org/article/35d451080f024fab83112a996cf37289
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Liposomal formulation of a methotrexate lipophilic prodrug: assessment in tumor cells and mouse T-cell leukemic lymphoma

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