背景:依维莫司是一种被批准用于治疗绝经后女性复发的HR+乳腺癌和晚期乳腺癌的药物。已经观察到EVE的口服施用具有低的口服生物利用度和严重的上皮皮肤事件,所述事件包括皮疹和唇溃疡,然后是口服施用后的口腔溃疡。
目的:本研究旨在通过将EVE加载到用于静脉给药的隐形脂质体制剂(S-EVE-LIPO)中来提高生物利用度。
方法:脂质体表面用维生素ETPGS修饰,延长药物的体循环,并提供额外的好处,如抑制P-gp外排泵和与EVE协同作用。
结果:使用薄膜水合方法制备配方,并使用D-最佳混合物设计进行优化。方差分析提出了所提出的数学模型的重要性,并通过设计专家软件生成优化配方。观察到优化的制剂(S-EVE-LIPO)具有纳米尺寸(99.5±3.70nm),具有更高的包封效力(81.5±2.86%)。S-EVELIPO制剂显示出持续释放曲线,因为在48小时内观察到90.22%的药物释放,而不含维生素ETPGS(EVE-LIPO)的制剂在24小时内仅释放74.15种药物。体外细胞毒性研究表明,维生素ETPGS的存在降低了IC50值(54.2±1.69),增加制剂的细胞摄取,也增加了ROS的产生,并显示出更好的血液相容性。
结论:维生素ETPGS可以作为一种重要的添加剂,以提高治疗效果,减少异位毒性和给药频率。
Everolimus is a drug approved for the treatment of breast cancer with HR+ and advanced breast cancer reoccurring in postmenopausal women. The oral administration of EVE has been observed to have low oral bioavailability and severe epithelial cutaneous events that include rashes and lip ulceration followed by mouth ulceration after oral administration.
The present research aimed to enhance the bioavailability by loading the EVE into a stealth liposomal formulation (S-EVE-LIPO) intended for intravenous administration.
The surface of the liposomes was modified with vitamin E TPGS, which prolongs the systemic circulation of the drug and provides additional benefits like inhibition of the P-gp efflux pump and acting synergistically with EVE.
The formulation was prepared using the thin film hydration method and optimized using a D-optimal mixture design. ANOVA suggested the significance of the proposed mathematic model, and the optimized formulation was generated by design expert software. The optimized formulation (S-EVE-LIPO) was observed with nanometric size (99.5 ± 3.70 nm) with higher encapsulation efficacy (81.5 ± 2.86 %). The S-EVELIPO formulation indicated a sustained release profile as 90.22% drug release was observed in 48 h, whereas the formulation without vitamin E TPGS (EVE-LIPO) released only 74.15 drugs in 24 hours. In vitro cytotoxicity study suggested that the presence of vitamin E TPGS lowers the IC50 value (54.2 ± 1.69), increases the cellular uptake of the formulation, also increases the generation of ROS, and shows better hemocompatibility.
Vitamin E TPGS could be set as a vital additive to improve therapeutic efficacy and reduce offsite toxicity and dosing frequency.