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Biochim Biophys Acta. 2015 Aug;1848(8):1656-70. doi: 10.1016/j.bbamem.2015.04.011. Epub 2015 Apr 24.

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

Author information

1
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Center, Rotterdam 3000 CA, The Netherlands.
2
Optical Imaging Center, Department of Pathology, Erasmus MC, Rotterdam 3000 CA, The Netherlands.
3
Unidad de Biofísica (CSIC, UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain; Departamento de Bioquímica, Universidad del País Vasco, P.O. Box 644, 48080 Bilbao, Spain.
4
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Center, Rotterdam 3000 CA, The Netherlands; Institut de Cancerologie Gustave Roussy, Villejuif, Paris 94800, France.
5
Division of Biological Stress Response, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, The Netherlands; Department of Radiotherapy, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, The Netherlands.
6
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Center, Rotterdam 3000 CA, The Netherlands. Electronic address: g.koning@erasmusmc.nl.
7
Unidad de Biofísica (CSIC, UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain; Departamento de Bioquímica, Universidad del País Vasco, P.O. Box 644, 48080 Bilbao, Spain; IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain. Electronic address: xabier.contreras@ehu.es.

Abstract

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.

KEYWORDS:

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

PMID:
25917957
DOI:
10.1016/j.bbamem.2015.04.011
[Indexed for MEDLINE]
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