Abstract
Abstract
Background: Interstitial and vascular targeting with cytotoxic agents has proven to be an effective approach for cancer therapy (1). Ceramide, a sphingolipid, plays an important role in apoptosis, regulation of differentiation, growth suppression, and in cell senescence (2). Liposomes containing ceramide exert an anti-proliferative effect against the growth of tumor cells in vitro (3). In this study, we attempted to apply a rational approach to the development of ceramide liposomes for tumor targeting.
Methods: We first determined the relative amounts of ceramide produced by cells normally found in the tumor interstitial matrix (ZR-75-1- human breast cancer cells), and by those lining tumor endothelia (HMEC-1 -human microvascular endothelial cells). For this experiment we measured sphingomyelinase activity. We next determined the cytotoxic effects of various liposome systems containing 0 to 20% ceramide (C6:1) content. The optimal ceramide content was determined from this study, and 2-methoxyestradiol (2-ME) was loaded in the optimal ceramide liposome preparation type. We next evaluated cytotoxic effects of the drug-loaded liposomes compared to ceramide liposomes alone.
Results: ZR-75-1 cells showed a higher level of sphingomyelinase activity (4.4 fold) as compared to that of HMEC-1. The 20% ceramide formulation demonstrated the most significant anti-proliferative effect, regardless of the cell line. The cytotoxic drug effects were favorably influenced by the ceramide content. Finally, preliminary studies suggest that the overall effectiveness of ceramide liposomes against the growth of proliferating tumor cells correlated with the sphingomyelinase activity expressed by the target cells.
Conclusion: Future studies will determine whether sphingomyelinase activity can be used to determine the population of cells (i.e., interstitial vs vascular) most likely to benefit from ceramide (cytotoxic) drug-loaded liposomes as a therapeutic approach.
Citation Format: Shaohua Cheng, William Crall, Bryan Nguyen, Charles Dang, Musaed Alkholief, Robert B. Campbell. Development of ceramide liposomes for tumor interstitial and vascular drug targeting. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4473. doi:10.1158/1538-7445.AM2014-4473