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BMC Proceedings

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Short-chain sphingolipids for enhanced cellular uptake of liposome-encapsulated amphiphilic anti-cancer drugs

  • Lília RC Pedrosa1Email author,
  • Albert van Hell2,
  • Wim van Blitterswijk2,
  • Ann LB Seynhaeve1,
  • Alexander MM Eggermont1,
  • Timo LM ten Hagen1,
  • Marcel Verheij2, 3 and
  • Gerben A Koning1
BMC Proceedings20104(Suppl 2):P39

Published: 24 September 2010


Endothelial CellDoxorubicinTumor Cell LineCellular UptakeDrug Uptake

Short-chain sphingolipids, such as C8-Glucosylceramide (C8-GC) have been described to enhance the cellular uptake of amphiphilic drugs, in free form or when co-formulated in liposomes (1,2). The involved mechanism is currently unknown, but is hypothesized to induce domain or pore formation in the plasma membrane (3). The aim of this study is to further explore this specific drug uptake process by C8-GC to enhance intracellular delivery of liposomal doxorubicin.

Liposomes, containing different percentages of incorporated C8-GC were prepared and loaded with doxorubicin. Characterization was performed by measuring size, polydispersity index (pdi), phospholipid and doxorubicin content. In vitro anti-tumor activity was studied towards a panel of human tumor cell lines and normal cells: endothelial cells and fibroblasts.

Doxorubicin liposomes (Dox-L) enriched with 10 mol% C8-GC presented less fluctuation in size and pdi than 15 mol% and efficiently retained their contents under culture conditions (10% serum). In all tumor cell lines tested C8-GC-Dox-L exerted increased cytotoxicity, resulting in up to 20 fold lower IC50 values compared to standard Dox-L. This effect was not observed with endothelial cells and with fibroblasts it was much less pronounced.

In conclusion, 10 mol% C8-GC-enriched Dox-L had optimal stability and showed enhanced cytotoxicity towards tumor cells and not towards normal cells. Based on these findings, modification of Dox-L formulations with 10 mol% of C8-GC can be used to improve drug delivery to tumor cells.

Authors’ Affiliations

Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC- Daniel den Hoed Cancer Center, Rotterdam, The Netherlands
Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands


  1. Veldman RJ, Zerp S, van Blitterswijk WJ, Verheij M: N-hexanoyl-sphingomyelin potentiates in vitro doxorubicin cytotoxicity by enhancing its cellular influx. Br J Cancer. 2004, 90: 917-925. 10.1038/sj.bjc.6601581.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Veldman RJ, Koning GA, van Hell A, Zerp S, Vink SR, Storm G, Verheij M, van Blitterswijk WJ: Coformulated N-octanoyl-glucosylceramide improves cellular delivery and cytotoxicity of liposomal doxorubicin. J Pharmacol Exp Ther. 2005, 315: 704-710. 10.1124/jpet.105.087486.View ArticlePubMedGoogle Scholar
  3. Siskind LJ: Mitochondrial ceramide and the induction of apoptosis. J Bioenerg Biomembr. 2005, 37: 143-153. 10.1007/s10863-005-6567-7.PubMed CentralView ArticlePubMedGoogle Scholar


© Pedrosa et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.