Abstract 2761: Co-administration of the short-chain sphingolipid N-octanoyl-glucosylceramide improves doxorubicin therapy by enhancing intracellular drug accumulation in vivo

Abstract

Abstract BACKGROUND: Plasma membranes are a effective barrier that prevent exogenous therapeutics, including cytostatic drugs, to reach their intracellular targets and become active. Membrane traversal of most drugs is therefore sub-optimal and remains a major limitation for clinical efficacy. We identified a well-defined class of short-chain lipids that modulate the plasma membrane and facilitate the cellular accumulation of amphiphilic drugs, including doxorubicin. RESULTS: A liposomal co-formulation of the short-chain lipid N-octanoylglucosylceramide (GC) and doxorubicin was applied in a genetically engineered mouse (GEM) breast tumor model (Wcre;Cdh1F/F;Trp53F/F). These tumors, which are resistant to a variety of conventional and biological cytostatic therapies, responded to doxorubicin treatment when combined with the membrane modulation strategy. Co-administration of GC generated a sustained anti-tumor response and significantly improved overall survival (30 days versus 11 days for control; p < 0.005). Using a nuclear isolation procedure, we showed that the presence of GC enhanced the intracellular tumor accumulation in vivo by a factor 1.9 (p < 0.05). In contrast, the accumulation within normal heart tissue was not elevated. The latter data are in agreement with in vitro experiments using cultured cardiac myocytes. When compared to either clinically available formulations of doxorubicin (free or PEGylated liposomal doxorubicin) a favorable efficacy, pharmacokinetic and toxicity profile was obtained by co-formulation of GC with doxorubicin. CONCLUSION: The short-chain sphingolipid GC improves the therapeutic ratio in multi-drug resistant GEM breast tumors by enhancing the intracellular tumor accumulation of doxorubicin while limiting normal tissue exposure. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2761. doi:1538-7445.AM2012-2761