In vitro
tumor cell culture models have illuminated the potential therapeutic utility of elevating the intracellular concentration of the antimitogenic and proapoptotic
sphingolipid,
ceramide. However, although cell-permeable, short-chain
ceramide is an effective apoptotic agent in vitro, its use as an in vivo, systemically delivered therapeutic is limited by its inherent
lipid hydrophobicity and physicochemical properties. Here, we report that the systemic i.v. delivery of
C6-ceramide (C6) in a pegylated liposomal formulation significantly limited the growth of solid
tumors in a syngeneic BALB/c mouse
tumor model of breast
adenocarcinoma. Over a 3-week treatment period, a well-tolerated dose of 36 mg/kg liposomal-C6 elicited a >6-fold reduction in
tumor size compared with empty ghost
liposomes. Histologic analyses of solid
tumors from liposomal-C6-treated mice showed a marked increase in the presence of apoptotic cells, with a coincident decrease in cellular proliferation and in the development of a microvessel network. Liposomal-C6 accumulated within caveolae and mitochondria, suggesting putative mechanisms by which
ceramide induces selective
cancer cell cytotoxicity. A pharmacokinetic analysis of systemic liposomal-C6 delivery showed that the pegylated liposomal formulation follows first-order kinetics in the blood and achieves a steady-state concentration in
tumor tissue. Confirming the therapeutic utility of i.v. liposomal-C6 administration, we also shown diminution of solid
tumor growth in a human xenograft model of
breast cancer. Together, these results indicate that bioactive
ceramide analogues can be incorporated into pegylated liposomal vehicles for improved solubility,
drug delivery, and
antineoplastic efficacy.