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

Lilia Cordeiro Pedrosa, A van Hell, R Suss, WJ van Blitterswijk, Ann Seynhaeve, Gert van Cappellen, Lex Eggermont, Timo ten Hagen, M Verheij, Gerben Koning

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)


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). 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 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. 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.
Original languageUndefined/Unknown
Pages (from-to)1883-1895
Number of pages13
JournalPharmaceutical Research
Issue number7
Publication statusPublished - 2013

Cite this