Liposomes loaded with daunorubicin and an emetine prodrug for improved selective cytotoxicity towards acute myeloid leukaemia cells.

The backbone of induction therapy in acute myeloid leukaemia (AML) is to use an anthracycline in combination with cytarabine. Despite recent advances in AML therapy, this treatment remains the standard, and it has been largely unchanged for decades. There are few curative options for patients unfit for this treatment. The anti-protozoal agent emetine improves efficacy of anthracycline treatment towards AML in vitro and in vivo but the effect is more potent when emetine is administered 30 minutes after anthracyclines. To delay the onset of protein synthesis inhibition we produced a novel inactive emetine prodrug and co-encapsulated this with the anthracycline daunorubicin (DNR) in liposomes. Nanoencapsulation protects the prodrug from degradation in the blood and ensure simultaneous delivery of both drugs to cancer cells. The prodrug concept will delay the onset of action of emetine relative to DNR. In AML cells, the combination of DNR and the emetine-prodrug in liposomes increased cytotoxicity compared to liposomes with DNR and native emetine. Liposomes loaded with the emetine prodrug did not show increased toxicity towards non-cancerous cell lines and zebrafish larvae. In patients, a liposomal formulation such as that presented herein could allow for a reduced DNR dose without compromising efficacy, thereby reducing toxic side effects and enabling improved therapy for patients not fit for current treatment options.