Liposomal formulation of alpha-tocopheryl maleamide: in vitro and in vivo toxicological profile and anticancer effect against spontaneous breast carcinomas in mice.
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.
Turánek
Jaroslav
J
Department of Vaccinology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic. turanek@vri.cz
Wang
Xiu-Fang
XF
Knötigová
Pavlína
P
Koudelka
Stepán
S
Dong
Lan-Feng
LF
Vrublová
Eva
E
Mahdavian
Elahe
E
Procházka
Lubomír
L
Sangsura
Smink
S
Vacek
Antonín
A
Salvatore
Brian A
BA
Neuzil
Jiri
J
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
D000970:Antineoplastic Agents; D008081:Liposomes; D008301:Maleimides; D014810:Vitamin E; D011092:Polyethylene Glycols; D024502:alpha-Tocopherol; C014225:tocophersolan