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

Алексеева, А. С.; Моисеева, Е. В.; Onishchenko, Natalia; Болдырев, Иван; Singin, A. S.; Budko, Andrey; Shprakh, Z. S.; Molotkovsky, Julian G.; Водовозова, Е. Л.

doi:10.2147/ijn.s133034

Cited by 26 publications

(30 citation statements)

References 38 publications

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“…The influence of the preparation method of liposomes was also evaluated using the remote loading. However, this approach can only be applied to weak amphipathic acids or bases, which MTX molecule does not belong to Alekseeva et al (2017). Liposomes encapsulating DOX, prepared by remote loading, was then used in this study, however, high leakage level is also observed (24.5%, Table 2).…”

Section: Influence Of the Freeze-drying On Drug Leakage From Liposomesmentioning

confidence: 99%

Protective Effect of Saccharides on Freeze-Dried Liposomes Encapsulating Drugs

Guimarães

Noro

Silva

et al. 2019

Front. Bioeng. Biotechnol.

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The production of freeze-dried liposomes encapsulating drugs is considered a key challenge since the drugs are prone to leakage. The aim of this work was to study the effect of different saccharides on preserving the stability and drug retention capacity of a previously developed liposomal formulation, when subjected to a freeze-drying process. The protective role of trehalose, lactose, glucose, mannitol and sucrose, known for their cryo/lyoprotective effect, was tested by addition of different concentrations to liposomes. Sucrose, in a concentration dependent manner (8:1 sugar:lipids mass ratio) proved to be a suitable cryo/lyoprotectant of these liposomes. Effectively, this saccharide prevents the fusion or/and aggregation of the liposomal formulation, protecting the integrity of the freeze-dried empty liposomes. The liposomal formulation containing sucrose was studied in terms of morphology, concentration, and anticancer drugs retention ability. The study involved two drugs encapsulated in the aqueous core, methotrexate (MTX) and doxorubicin (DOX), and one drug located in the lipid bilayer, tamoxifen (TAM). After the freeze-drying process, liposomes with sucrose encapsulating drugs revealed high physical stability, maintaining their narrow and monodisperse character, however high leakage of the drugs encapsulated in the aqueous core was observed. Otherwise, no significant drug leakage was detected on liposomes containing the TAM, which maintained its biological activity after the freeze-drying process. These findings reveal that sucrose is a good candidate for the cryo/lyoprotection of liposomes with drugs located in the lipid bilayer.

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Section: Influence Of the Freeze-drying On Drug Leakage From Liposomesmentioning

confidence: 99%

Protective Effect of Saccharides on Freeze-Dried Liposomes Encapsulating Drugs

Guimarães

Noro

Silva

et al. 2019

Front. Bioeng. Biotechnol.

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“…AUC ratios of various L-LDCs. [34 ], [39] , [10] , [25] , [40] , [32], [41] , [42] , [38] , [43] , [44], [45] , [46] , [4] , [47] , [48] , [49 ] , [50 ] , [ 51 ], [52 ] , [24 ] , [37 ] , [42 ] 3. PKs and biodistribution…”

Section: The Auc Ratio -A Means To Assess An L-ldcmentioning

confidence: 99%

“…Another example of immediate cleavage was provided in a study with a methotrexate-based LDC conjugated to a dioleoylglyceride-anchor with a linker structure containing two ester and an amide bond (Fig. 2, compound 13) [46].…”

Section: In Vivo Drug Release Of Ldcsmentioning

confidence: 99%

“…Upon systemic injection into healthy mice, the L-LDC rapidly released the parent drug indicated by a higher AUC of the parent drug compared to the one of the LDC (AUC ratios were 2.1 versus 0.9, respectively, Table 1, compound 13) [46]. This was not in line with an earlier in vitro study where the conjugate was said to be stable in human plasma for more than 24 h when entrapped in liposomes, and was explained by differences in interspecies enzyme activity [59].…”

Section: In Vivo Drug Release Of Ldcsmentioning

confidence: 99%

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Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Signorell

Luciani

Brambilla

et al. 2018

European Journal of Pharmaceutics and Biopharmaceutics

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Drugs that are neither lipophilic nor suitable for encapsulation via remote loading procedures are generally characterized by low entrapment efficiencies and poor retention in liposomes. One approach to circumvent this problem consists in covalently linking a lipid to the drug molecule in order to permit its insertion into the vesicle membrane. The nature of the conjugated lipid and linker, as well as the composition of the liposomal bilayer were found to have a profound impact on the pharmacokinetic properties and biodistribution of the encapsulated drugs as well as on their biological activity. This contribution reviews the past and recent developments on liposomal lipid-drug conjugates, and discusses important issues related to their stability and in vivo performance. It also provides an overview of the data that were generated during the clinical assessment of these formulations. The marketing authorization of the immunomodulating compound mifamurtide in several countries as well as the promising results obtained with the lipid prodrug of mitomycin C suggest that carefully designed liposomal formulations of lipid-drug conjugates is a valid strategy to improve a drug's pharmacokinetic profile and with that its therapeutic index and/or efficacy.

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“…В культуре RFC-дефицитных Т-лимфобластоидных клеток такие МТХ-липосомы преодолевали резистентность к МТХ [11]. В мышиной модели острого лейкемического варианта Т-клеточной лимфомы МТХлипосомы ингибировали рост опухоли эффективнее, чем интактный МТХ, и были менее токсичными [12].…”

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Lipophilic prodrug of methotrexate in the membrane of liposomes promotes their uptake by human blood phagocytes

et al. 2020

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Previously, we showed that incorporation of methotrexate (MTX) in the form of a lipophilic prodrug (MTXDG) in 100-nm lipid bilayer liposomes of egg phosphatidylcholine can allow one to reduce toxicity and improve the antitumor efficiency of MTX in a mouse model of T-cell leukemic lymphoma. However, in our hemocompatibility tests in vitro, MTX liposomes caused complement (C) activation, obviously due to binding on the liposome surface and fragmentation of the C3 complement factor. In this work, we studied the interactions of MTX liposomes carrying stabilizing molecules phosphatidylinositol (PI), ganglioside GM1, or a lipid conjugate of N-carboxymethylated oligoglycine (CMG) in the bilayer with subpopulations of human blood leukocytes. Liposomes labeled with BODIPY-phosphatidylcholine were incubated with whole blood (30 min and 1 h, 37C), blood cells were lysed with a hypotonic buffer, and the fluorescence of the liposomes bound but not internalized by the leukocytes was quenched by crystal violet. Cell suspensions were analyzed by flow cytometry. Incorporation of MTXDG dramatically enhanced the phagocytosis of liposomes of any composition by monocytes. Neutrophils consumed much less of the liposomes. Lymphocytes did not accumulate liposomes. The introduction of PI into MTX liposomes practically did not affect the specific consumption of liposomes by monocytes, while CMG was likely to increase the consumption rate regardless of the presence of MTXDG. The GM1 ganglioside presumably shielded MTX liposomes from phagocytosis by one of the monocyte populations and increased the efficiency of monocyte uptake by another population, probably one expressing C3b-binding receptors (C3b was detected on liposomes after incubation with blood plasma). MTX liposomes were shown to have different effects on TNF- production by activated leukocytes, depending on the structure of the stabilizing molecule.

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

Cited by 26 publications

References 38 publications

Protective Effect of Saccharides on Freeze-Dried Liposomes Encapsulating Drugs

Protective Effect of Saccharides on Freeze-Dried Liposomes Encapsulating Drugs

Pharmacokinetics of lipid-drug conjugates loaded into liposomes

Lipophilic prodrug of methotrexate in the membrane of liposomes promotes their uptake by human blood phagocytes

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