Liposomal formulation of alpha-tocopheryl maleamide: in vitro and in vivo toxicological profile and anticancer effect against spontaneous breast carcinomas in mice
Jazyk angličtina Země Spojené státy americké Médium print
Typ dokumentu srovnávací studie, časopisecké články, práce podpořená grantem
PubMed
19480910
DOI
10.1016/j.taap.2009.01.027
PII: S0041-008X(09)00059-3
Knihovny.cz E-zdroje
- MeSH
- alfa-tokoferol aplikace a dávkování analogy a deriváty farmakologie MeSH
- farmaceutická chemie MeSH
- lidé MeSH
- liposomy MeSH
- maleimidy aplikace a dávkování farmakologie MeSH
- melanom experimentální farmakoterapie patologie MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši transgenní MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prsu farmakoterapie patologie MeSH
- polyethylenglykoly aplikace a dávkování farmakologie MeSH
- protinádorové látky aplikace a dávkování farmakologie MeSH
- vitamin E aplikace a dávkování analogy a deriváty farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Názvy látek
- alfa-tokoferol MeSH
- liposomy MeSH
- maleimidy MeSH
- polyethylenglykoly MeSH
- protinádorové látky MeSH
- tocophersolan MeSH Prohlížeč
- vitamin E MeSH
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.
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