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

Journal Article · Mon Jun 15 04:00:00 UTC 2009 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2009.01.027· OSTI ID:21272575

Turanek, Jaroslav ^[1]; Xiufang, Wang ^[2]; Knoetigova, Pavlina; Koudelka, Stepan ^[1]; Lanfeng, Dong ^[2]; Vrublova, Eva ^[1]; Mahdavian, Elahe ^[3]; Prochazka, Lubomir ^[1]; Sangsura, Smink ^[3]; Vacek, Antonin ^[1]; Salvatore, Brian A ^[3]; Neuzil, Jiri ^[2]

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1. Department of Vaccinology and Immunotherapy, Veterinary Research Institute, Brno (Czech Republic)
2. Apoptosis Research Group, School of Medical Science, Griffith University, Southport, Qld (Australia)
3. Department of Chemistry, Louisiana State University, Shreveport, LA (United States)

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.

• OSTI ID: 21272575
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 3 Vol. 237; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
CARCINOMAS
CHLOROFLUOROCARBONS
DELIVERY
DMSO
DRUGS
IMPLANTS
IN VITRO
LECITHINS
LYMPHOCYTES
MACROPHAGES
MAMMARY GLANDS
MICE
TAMOXIFEN
TOXICITY
VITAMIN E