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 alpha-tocopheryl succinate (alpha-TOS) is an efficient anti-cancer drug. Improved efficacy was achieved through the synthesis of alpha-tocopheryl maleamide (alpha-TAM), an esterase-resistant analogue of alpha-tocopheryl maleate. In vitro tests demonstrated significantly higher cytotoxicity of alpha-TAM towards cancer cells (MCF-7, B16F10) compared to alpha-TOS and other analogues prone to esterase-catalyzed hydrolysis. However, in vitro models demonstrated that alpha-TAM was cytotoxic to non-malignant cells (e.g. lymphocytes and bone marrow progenitors). Thus we developed lyophilized liposomal formulations of both alpha-TOS and alpha-TAM to solve the problem with cytotoxicity of free alpha-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 alpha-TAM, which significantly reduced the growth of cancer cells in hollow fiber implants. Moreover, liposomal formulation of alpha-TAM and alpha-TOS each prevented the growth of tumours in transgenic FVB/N c-neu mice bearing spontaneous breast carcinomas. Liposomal formulation of alpha-TAM demonstrated anti-cancer activity at levels 10-fold lower than those of alpha-TOS. Thus, the liposomal formulation of alpha-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.

Lyophilised liposome‐based formulations of α‐tocopheryl succinate: Preparation and physico‐chemical characterisation

“…Their liposomal formulations were found to be well tolerated in mice of various strains and preserved the strong anticancer efficacy of the VE analogues, as shown using the transgenic FVB/N c-neu mice with spontaneous breast carcinomas. 26 Nonliposomal systems like vesiculated VE analogues formed by spontaneous vesiculation were found to be toxic for some analogues of VE, for example, a-tocopheryl oxalate, 18 or a-TAM. 26 Thus, entrapment of such analogues (as shown for a-TAM) minimises the secondary toxicity while the anticancer efficacy remains preserved.…”

“…26 Nonliposomal systems like vesiculated VE analogues formed by spontaneous vesiculation were found to be toxic for some analogues of VE, for example, a-tocopheryl oxalate, 18 or a-TAM. 26 Thus, entrapment of such analogues (as shown for a-TAM) minimises the secondary toxicity while the anticancer efficacy remains preserved. 26 Stable preparations of a-TOS and similar anticancer agents that could be stored for prolonged periods of time are needed.…”

“…26 Thus, entrapment of such analogues (as shown for a-TAM) minimises the secondary toxicity while the anticancer efficacy remains preserved. 26 Stable preparations of a-TOS and similar anticancer agents that could be stored for prolonged periods of time are needed. A plausible approach to this problem is the use of liposomes, which have been utilised as suitable carriers for a variety of drugs and vaccines.…”

“…Liposomal formulation of a-tocopheryl maleamide (a-TAM), an esterase-resistant analogue of the ester atocopheryl maleate, 25 was reported to eliminate the acute toxicity associated with administration of the free VE analogue. 26 The physico-chemical stability of liposomal nanoparticles depends on their composition and structure. Physical modifications of liposomes, including fusion and aggregation of the particles, as well as increase of the membrane permeability and the drug release can occur as the consequences of chemical degradation of the liposomal system.…”

Cytotoxic effect of palladium (II) inclusion compounds in beta-cyclodextrin

“…Las betaciclodextrinas son oligosacáridos cíclicos que forman complejos de inclusión en una variedad de moléculas hidrofóbicas (34), por lo cual se considera que confieren mayor solubilidad y estabilidad a las propiedades biológicas de las moléculas (30), efecto que se vería potenciado por las propiedades farmacológicas de los complejos de paladio (cuadro 1, 2) en la inhibición de la síntesis de ADN o por unión no covalente con el ADN, ocasionando así la muerte celular y logrando un mayor efecto con menores dosis, sin afectar de manera significativa las células linfoides normales.…”