title: Coformulated N-octanoyl-glucosylceramide improves cellular delivery and cytotoxicity of liposomal doxorubicin.
abstract: The anticancer agent doxorubicin is in certain cases administered as a long-circulating liposomal formulation. Due to angiogenesis-related structural abnormalities in the endothelial lining of many neoplasms, these complexes tend to extravasate and accumulate in the tumor stroma. However, delivery of doxorubicin is still not optimal since liposomes are not taken up directly by tumor cells. Instead, doxorubicin is gradually released into the interstitial space, and the subsequent uptake by surrounding cells is a limiting step in the delivery process. We recently demonstrated that plasma membrane-inserted short-chain sphingomyelin facilitates the cellular uptake of free doxorubicin. Here, we report that N-octanoyl-glucosylceramide acts equally potent but is itself less toxic. When coformulated with liposomal doxorubicin, this short-chain glycosphingolipid administered to cultured A431 epidermoid carcinoma cells led to superior (up to 4-fold) cellular doxorubicin accumulation and cytotoxicity, compared with control doxorubicin liposomes. These results were fully reproducible when N-octanoyl-glucosylceramide was postinserted into Caelyx, a commercial liposomal doxorubicin preparation. The doxorubicin-potentiating effect of N-octanoyl-glucosylceramide-enriched liposomes proved relatively insensitive to high serum concentrations, indicating that in vivo application is a feasible option. N-Octanoyl-glucosylceramide enrichment might thus represent a major improvement of conventional liposomal doxorubicin formulations.
authors.affiliation: Division of Cellular Biochemistry, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.
authors.forename: Robert Jan
authors.initials: RJ
authors.lastname: Veldman
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
authors.forename: Albert
authors.initials: A
authors.lastname: van Hell
authors.forename: Shuraila
authors.initials: S
authors.lastname: Zerp
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Vink
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.forename: Marcel
authors.initials: M
authors.lastname: Verheij
authors.forename: Wim J
authors.initials: WJ
authors.lastname: van Blitterswijk
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005963:Glucosylceramides / Q000494:pharmacology*; D006801:Humans; D008081:Liposomes; D008856:Microscopy, Fluorescence; D010743:Phospholipids
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D005963:Glucosylceramides; D008081:Liposomes; C506839:N-octanoylglucosylceramide; D010743:Phospholipids; D004317:Doxorubicin