Improving Intracellular Doxorubicin Delivery Through Nanoliposomes Equipped with Selective Tumor Cell Membrane Permeabilizing Short-Chain Sphingolipids

Purpose To improve nanoliposomal-doxorubicin (DoxNL) delivery in tumor cells using liposome membrane-incorporated short-chain sphingolipids (SCS) with selective membrane-permeabilizing properties. DoxNL bilayers contained synthetic short-chain derivatives of known membrane microdomain-forming sphing...

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Bibliographic Details
Published in:Pharmaceutical research 2013-07, Vol.30 (7), p.1883-1895
Main Authors: Pedrosa, Lília R. Cordeiro, van Hell, Albert, Süss, Regine, van Blitterswijk, Wim J., Seynhaeve, Ann L. B., van Cappellen, Wiggert A., Eggermont, Alexander M. M., ten Hagen, Timo L. M., Verheij, Marcel, Koning, Gerben A.
Format: Article
Language:English
Subjects:
Antibiotics, Antineoplastic - administration & dosage
Antibiotics, Antineoplastic - pharmacokinetics
Biochemistry
Biological and medical sciences
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Cancer
Cell Line, Tumor
Cell Membrane - drug effects
Cell Membrane Permeability - drug effects
Cellular biology
Doxorubicin - administration & dosage
Doxorubicin - pharmacokinetics
Drug delivery systems
Galactosylceramides - chemistry
Galactosylceramides - metabolism
Glucosylceramides - chemistry
Glucosylceramides - metabolism
Humans
Lactosylceramides - chemistry
Lactosylceramides - metabolism
Lipids
Liposomes - chemistry
Liposomes - metabolism
Medical Law
Medical sciences
Membranes
Nanoparticles
Neoplasms - drug therapy
Pharmaceutical sciences
Pharmacology. Drug treatments
Pharmacology/Toxicology
Pharmacy
Research Paper
Sphingolipids - chemistry
Sphingolipids - metabolism
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Summary:Purpose To improve nanoliposomal-doxorubicin (DoxNL) delivery in tumor cells using liposome membrane-incorporated short-chain sphingolipids (SCS) with selective membrane-permeabilizing properties. DoxNL bilayers contained synthetic short-chain derivatives of known membrane microdomain-forming sphingolipids; C 8 -glucosylceramide (C 8 -GluCer), C 8 -galactosylceramide (C 8 -GalCer) or C 8 -lactosylceramide (C 8 -LacCer). Methods DoxNL enriched with C 8 -GluCer or C 8 -GalCer were developed, optimized and characterized with regard to size, stability and drug retention. In vitro cytotoxic activity was studied in a panel of human tumor cell lines and normal cells. Intracellular Dox delivery was measured by flow cytometry and visualized by fluorescence microscopy. For a further understanding of the involved drug delivery mechanism confocal microscopy studies addressed the cellular fate of the nanoliposomes, the SCS and Dox in living cells. Results C 8 -LacCer-DoxNL aggregated upon Dox loading. In tumor cell lines SCS-DoxNL with C 8 -GluCer or C 8 -GalCer demonstrated strongly increased Dox delivery and cytotoxicity compared to standard DoxNL. Surprisingly, this effect was much less pronounced in normal cells. Nanoliposomes were not internalized, SCS however transfered from the nanoliposomal bilayer to the cell membrane and preceded cellular uptake and subsequent nuclear localization of Dox. Conclusion C 8 -GluCer or C 8 -GalCer incorporated in DoxNL selectively improved intracellular drug delivery upon transfer to tumor cell membranes by local enhancement of cell membrane permeability.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-013-1031-6