Synthesis of a Lipid Derivative of the Antitumor Agent Methotrexate

Водовозова, Е. Л.; Evdokimov, D. V.; Molotkovskiĭ, Iu G

doi:10.1023/b:rubi.0000049779.60159.c5

Cited by 7 publications

(2 citation statements)

References 6 publications

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“…rac-1,2-Dioleoylglyceride ester conjugate of MTX (MTX-DG), 17 1-palmitoyl-2-[7-(Me 4 -BODIPY-8)heptanoyl]-sn-glycero-3-phosphocholine (BODIPY-PC), 18 and BODIPY-labeled analog of MTX-DG (BODIPY-MTX-DG) 19 ( Figure 1) were synthesized as previously reported. Inorganic salts, ethylenediaminetetraacetic acid (EDTA), chlorpromazine, cytochalasin B, colchicine, and nocodazole were purchased from Sigma Aldrich.…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

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

Алексеева¹,

Моисеева²,

Onishchenko³

et al. 2017

IJN

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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.

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Section: Materials and Methods Materialsmentioning

confidence: 99%

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

Алексеева¹,

Моисеева²,

Onishchenko³

et al. 2017

IJN

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“…For instance, a lipophilic prodrug of MTX was synthesized by coupling it to the rac-1,2-dioeloylglycerol through ester linkage and further incorporated into liposomes. 135,136 These MTX liposomes achieved a 114-fold decrease in resistance to MTX in human leukemia cell lines that were characterized by the decreased activity of RFCs. However, some safety issues such as complement activation and reduction in plasma clotting were associated with these liposomes.…”

Section: Impaired Drug Uptakementioning

confidence: 99%

How can nanomedicines overcome cellular-based anticancer drug resistance?

2016

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Despite the great progress in the field of cancer research, complete remission of cancer patients is a rarely seen outcome in clinics. The failure of a plethora of promising anticancer drugs is mostly due to the insurgence of multidrug resistance (MDR) phenomena with various factors, both physio-pathological and cellular, being responsible for their development. Over the past 40 years, the impressive progress in the nanotechnology field and its application in medicine (i.e., nanomedicine) enabled the development of novel cancer treatments with improved specificity and efficacy, mainly referring to the possibility to overcome MDR. However, the emergence of many nanomedicines defined in the literature as ''overcoming the resistance'' has resulted in very few of them eventually being approved for clinical application and reaching the marketplace (liposomal formulation of doxorubicin (Myocet s , Caelix s ) and paclitaxel nanoparticles (Abraxane s ), for instance). The capacity of nanomedicines to overcome physio-pathologicalbased resistance by enhancing drug accumulation at the tumor site via passive and ligand-mediated targeting has been largely reviewed in the past few years. This review will specifically focus on the cellular mechanisms involved in the MDR, which will be discussed with respect to the cellular site in which their action is exerted (that is, membrane, cytoplasm or nucleus). A complete overview of various nanomedicines designed to bypass or directly inhibit each of these specific resistance mechanisms will be offered.

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