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

Authors Alekseeva AA, Moiseeva EV, Onishchenko NR, Boldyrev IA, Singin AS, Budko AP, Shprakh ZS, Molotkovsky JG, Vodovozova EL

Received 23 January 2017

Accepted for publication 6 April 2017

Published 15 May 2017 Volume 2017:12 Pages 3735—3749

DOI https://doi.org/10.2147/IJN.S133034

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 4

Editor who approved publication: Professor Israel (Rudi) Rubinstein


Anna A Alekseeva,1 Ekaterina V Moiseeva,1 Natalia R Onishchenko,1 Ivan A Boldyrev,1 Alexander S Singin,2,† 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

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
Corrigendum for this paper has been published 

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