C8-glycosphingolipids preferentially insert into tumor cell membranes and promote chemotherapeutic drug uptake

Lília R. Cordeiro Pedrosa, Wiggert A. Van Cappellen, Barbara Steurer, Dalila Ciceri, Timo L.M. Ten Hagen, Alexander M.M. Eggermont, Marcel Verheij, Felix María Goñi, Gerben A. Koning, F. Xabier Contreras

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6 Citations (Scopus)


Insufficient drug delivery into tumor cells limits the therapeutic efficacy of chemotherapy. Co-delivery of liposome-encapsulated drug and synthetic short-chain glycosphingolipids (SC-GSLs) significantly improved drug bioavailability by enhancing intracellular drug uptake. Investigating the mechanisms underlying this SC-GSL-mediated drug uptake enhancement is the aim of this study. Fluorescence microscopy was used to visualize the cell membrane lipid transfer intracellular fate of fluorescently labeled C6-NBD-GalCer incorporated in liposomes in tumor and non-tumor cells. Additionally click chemistry was applied to image and quantify native SC-GSLs in tumor and non-tumor cell membranes. SC-GSL-mediated flip-flop was investigated in model membranes to confirm membrane-incorporation of SC-GSL and its effect on membrane remodeling. SC-GSL enriched liposomes containing doxorubicin (Dox) were incubated at 4 °C and 37 °C and intracellular drug uptake was studied in comparison to standard liposomes and free Dox. SC-GSL transfer to the cell membrane was independent of liposomal uptake and the majority of the transferred lipid remained in the plasma membrane. The transfer of SC-GSL was tumor cell-specific and induced membrane rearrangement as evidenced by a transbilayer flip-flop of pyrene-SM. However, pore formation was measured, as leakage of hydrophilic fluorescent probes was not observed. Moreover, drug uptake appeared to be mediated by SC-GSLs. SC-GSLs enhanced the interaction of doxorubicin (Dox) with the outer leaflet of the plasma membrane of tumor cells at 4 °C. Our results demonstrate that SC-GSLs preferentially insert into tumor cell plasma membranes enhancing cell intrinsic capacity to translocate amphiphilic drugs such as Dox across the membrane via a biophysical process.

Original languageEnglish
Pages (from-to)1656-1670
Number of pages15
JournalBiochimica et Biophysica Acta - Biomembranes
Issue number8
Publication statusPublished - 24 Apr 2015
Externally publishedYes


  • Doxorubicin
  • Liposome
  • Short-chain glycosphingolipid
  • Targeting tumor cell membrane
  • Tumor-cell membrane-permeability modulation


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