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This article is part of the supplement: Abstracts of the 16th International Charles Heidelberger Symposium on Cancer Research

Open Access Poster presentation

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

Lília RC Pedrosa1*, Albert van Hell2, Wim van Blitterswijk2, Ann LB Seynhaeve1, Alexander MM Eggermont1, Timo LM ten Hagen1, Marcel Verheij23 and Gerben A Koning1

Author Affiliations

1 Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC- Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

2 Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands

3 Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands

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BMC Proceedings 2010, 4(Suppl 2):P39  doi:10.1186/1753-6561-4-S2-P39


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1753-6561/4/S2/P39


Published:24 September 2010

© 2010 Pedrosa et al; licensee BioMed Central Ltd.

Poster presentation

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.

References

  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. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  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. PubMed Abstract | Publisher Full Text OpenURL

  3. Siskind LJ: Mitochondrial ceramide and the induction of apoptosis.

    J Bioenerg Biomembr 2005, 37:143-153. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL