Liposomal formulation of α-tocopheryl maleamide: In vitro and in vivo toxicological profile and anticancer effect against spontaneous breast carcinomas in mice

Abstract

The vitamin E analogue a-tocopheryl succinate (a-TOS) is an efficient anti-cancer drug. Improved efficacy was achieved through the synthesis of a-tocopheryl maleamide (a-TAM), an esterase-resistant analogue of a-tocopheryl maleate. In vitro tests demonstrated significantly higher cytotoxicity of a-TAM towards cancer cells (MCF-7, B16F10) compared to a-TOS and other analogues prone to esterase-catalyzed hydrolysis. However, in vitro models demonstrated that a-TAM was cytotoxic to non-malignant cells (e.g. lymphocytes and bone marrow progenitors). Thus we developed lyophilized liposomal formulations of both a-TOS and a- TAM to solve the problem with cytotoxicity of free a-TAM (neurotoxicity and anaphylaxis), as well as the low solubility of both drugs. Remarkably, neither acute toxicity nor immunotoxicity implicated by in vitro tests was detected in vivo after application of liposomal a-TAM, which significantly reduced the growth of cancer cells in hollow fiber implants. Moreover, liposomal formulation of a-TAM and a-TOS each prevented the growth of tumours in transgenic FVB/N c-neu mice bearing spontaneous breast carcinomas. Liposomal formulation of a-TAM demonstrated anti-cancer activity at levels 10-fold lower than those of a-TOS. Thus, the liposomal formulation of a-TAM preserved its strong anti-cancer efficacy while eliminating the in vivo toxicity found of the free drug applied in DMSO. Liposome-based targeted delivery systems for analogues of vitamin E are of interest for further development of efficient and safe drug formulations for clinical trials.