TY - JOUR
T1 - Improving intracellular doxorubicin delivery through nanoliposomes equipped with selective tumor cell membrane permeabilizing short-chain sphingolipids
AU - Pedrosa, Lília R.Cordeiro
AU - Van Hell, Albert
AU - Süss, Regine
AU - Van Blitterswijk, Wim J.
AU - Seynhaeve, Ann L.B.
AU - Van Cappellen, Wiggert A.
AU - Eggermont, Alexander M.M.
AU - Ten Hagen, Timo L.M.
AU - Verheij, Marcel
AU - Koning, Gerben A.
N1 - Funding Information:
This work was financed by the Dutch Cancer Society.
PY - 2013/7
Y1 - 2013/7
N2 - 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; C8-glucosylceramide (C8-GluCer), C8- galactosylceramide (C8-GalCer) or C8-lactosylceramide (C8-LacCer). Methods: DoxNL enriched with C8-GluCer or C8-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: C8-LacCer-DoxNL aggregated upon Dox loading. In tumor cell lines SCS-DoxNL with C8-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 C8-GalCer incorporated in DoxNL selectively improved intracellular drug delivery upon transfer to tumor cell membranes by local enhancement of cell membrane permeability.
AB - 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; C8-glucosylceramide (C8-GluCer), C8- galactosylceramide (C8-GalCer) or C8-lactosylceramide (C8-LacCer). Methods: DoxNL enriched with C8-GluCer or C8-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: C8-LacCer-DoxNL aggregated upon Dox loading. In tumor cell lines SCS-DoxNL with C8-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 C8-GalCer incorporated in DoxNL selectively improved intracellular drug delivery upon transfer to tumor cell membranes by local enhancement of cell membrane permeability.
KW - doxorubicin-nanoliposome
KW - short chain sphingolipid
KW - Tumor cell membrane permeabilization
UR - http://www.scopus.com/inward/record.url?scp=84878837344&partnerID=8YFLogxK
U2 - 10.1007/s11095-013-1031-6
DO - 10.1007/s11095-013-1031-6
M3 - Article
AN - SCOPUS:84878837344
SN - 0724-8741
VL - 30
SP - 1883
EP - 1895
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 7
ER -