title: Liposomal formulation of alpha-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.
authors.affiliation: Department of Vaccinology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic. turanek@vri.cz
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Turánek
authors.forename: Xiu-Fang
authors.initials: XF
authors.lastname: Wang
authors.forename: Pavlína
authors.initials: P
authors.lastname: Knötigová
authors.forename: Stepán
authors.initials: S
authors.lastname: Koudelka
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.forename: Eva
authors.initials: E
authors.lastname: Vrublová
authors.forename: Elahe
authors.initials: E
authors.lastname: Mahdavian
authors.forename: Lubomír
authors.initials: L
authors.lastname: Procházka
authors.forename: Smink
authors.initials: S
authors.lastname: Sangsura
authors.forename: Antonín
authors.initials: A
authors.lastname: Vacek
authors.forename: Brian A
authors.initials: BA
authors.lastname: Salvatore
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D005260:Female; D006801:Humans; D008081:Liposomes; D008301:Maleimides / Q000008:administration & dosage / Q000494:pharmacology; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology; D014810:Vitamin E / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D008301:Maleimides; D014810:Vitamin E; D011092:Polyethylene Glycols; D024502:alpha-Tocopherol; C014225:tocophersolan