Abstract 5527: Short-chain glucosylceramide improves doxorubicin delivery in spontaneous mouse breast carcinomas

Abstract

Abstract Background: Insufficient delivery of chemotherapeutic agents to their intended intracellular targets within the tumor remains a major obstacle in clinical oncology. Most of these drugs are amphiphilic and their diffusion through the plasma membrane is, therefore, slow and a major limitation for sufficient uptake within the tumor cell. We have found that certain short-chain sphingolipids enhance the intratumoral drug accumulation by modulation of inward translocation of cytostatics over the plasma membrane. Here, we examine this novel approach in an in vivo mouse model of aggressive invasive lobular breast carcinoma (ILC), designed to closely mimic its human counterpart. Results: In a panel of cell lines, short-chain sphingolipids, such as C8-glucosylceramide (GC) increase the intracellular accumulation of doxorubicin up to 4-fold. A clinically approved drug carrier (100 nm liposomes) was employed for co-delivery of both lipid and drug to the tumor tissue. The addition of 10 mol% GC markedly enhanced the cellular doxorubicin content in vivo, as was demonstrated with intravital fluorescence microscopy. In the metastatic and aggressive mouse ILC tumors, the efficacy of GC doxorubicin liposomes was significantly improved compared to the currently applied conventional doxorubicin liposomes. The enrichment with the GC membrane modulator resulted in a significant tumor growth delay (p = 0.0119) and an overall survival benefit (p = 0.0143) for mice treated with the GC enriched liposomal doxorubicin as compared to conventional liposomes. Conclusion: Short-chain sphingolipids improve the translocation of various cytostatics, including doxorubicin, over the plasma membrane of tumor cells. This membrane modulating strategy can be successfully applied in vivo, e.g. as a co-formulation with doxorubicin liposomes, thereby enhancing their anti-tumor efficacy. Furthermore, our data suggest that GC-enriched doxorubicin liposomes hold promise as anti-neoplastic therapy in human breast cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5527.