Turánek Jaroslav, Wang Xiu-Fang, Knötigová Pavlína, Koudelka Stepán, Dong Lan-Feng, Vrublová Eva, Mahdavian Elahe, Procházka Lubomír, Sangsura Smink, Vacek Antonín, Salvatore Brian A, Neuzil Jiri
Department of Vaccinology and Immunotherapy, Veterinary Research Institute, Brno, Czech Republic.
Toxicol Appl Pharmacol. 2009 Jun 15;237(3):249-57. doi: 10.1016/j.taap.2009.01.027.
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.
维生素E类似物琥珀酸α-生育酚酯（α-TOS）是一种有效的抗癌药物。通过合成马来酰胺α-生育酚酯（α-TAM）实现了疗效的提高，α-TAM是一种抗酯酶的马来酸α-生育酚酯类似物。体外试验表明，与α-TOS和其他易于酯酶催化水解的类似物相比，α-TAM对癌细胞（MCF-7、B16F10）具有显著更高的细胞毒性。然而，体外模型表明，α-TAM对非恶性细胞（如淋巴细胞和骨髓祖细胞）具有细胞毒性。因此，我们开发了α-TOS和α-TAM的冻干脂质体制剂，以解决游离α-TAM的细胞毒性问题（神经毒性和过敏反应）以及两种药物的低溶解度问题。值得注意的是，应用脂质体α-TAM后，体内未检测到体外试验所暗示的急性毒性和免疫毒性，脂质体α-TAM显著降低了中空纤维植入物中癌细胞的生长。此外，α-TAM和α-TOS的脂质体制剂均能抑制携带自发性乳腺癌的转基因FVB/N c-neu小鼠体内肿瘤的生长。α-TAM的脂质体制剂在比α-TOS低10倍的剂量水平下仍表现出抗癌活性。因此，α-TAM的脂质体制剂在保留其强大抗癌功效的同时，消除了在二甲基亚砜中应用游离药物时所发现的体内毒性。基于脂质体的维生素E类似物靶向递送系统对于进一步开发用于临床试验的高效安全药物制剂具有重要意义。
