Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Tecnología Farmacéutica I, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Química Biológica, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.
Biomed Pharmacother. 2017 Nov;95:894-903. doi: 10.1016/j.biopha.2017.09.006. Epub 2017 Sep 10.
Doxorubicin (DOX) is used as a "first-line" antineoplastic drug in ovarian and metastatic breast cancer. However, serious side effects, such as cardiotoxicity have been reported after DOX intravenous administration. Hence, we investigated different micelle-former biomaterials, as Soluplus, Pluronic F127, Tetronic T1107 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) to develop a potential mixed micellar nanocarrier for DOX delivery. Since DOX hydrochloride is a poor candidate to be encapsulated inside the hydrophobic core of the mixed micelles, we assayed a hydrophobic complex between DOX and sodium deoxycholate (NaDC) as an excellent candidate to be encapsulated within polymeric micelles. The combination of T1107:TPGS (1:3, weight ratio) demonstrated the best physicochemical properties together with a high DL capacity (6.43% w/v). Particularly, DOX in vitro release was higher at acidic tumour microenvironment pH value (5.5) than at physiological counterpart (7.4). The hydrodynamic diameter of the DOX/NaDC-loaded mixed micellar system was 10.7nm (PDI=0.239). The in vitro cytotoxicity of the mixed micellar formulation resulted significantly (p<0.05) higher than Doxil against ovarian (SKOV-3) and triple-negative breast cancer cells (MDA-MB- 231). Further, the in vitro cellular uptake assays demonstrated a significant increment (p<0.05) of the DOX intracellular content for the mixed micelles versus Doxil for both, SKOV-3 (at 2, 4 and 6h of incubation) and MDA-MB-231 (at 4h of incubation) cells. These findings suggest that T1107:TPGS (1:3) mixed micelles could be employed as a potential nanotechnological platform for drug delivery of DOX.
阿霉素（DOX）被用作卵巢癌和转移性乳腺癌的“一线”抗肿瘤药物。然而，静脉注射 DOX 后已报道严重的副作用，如心脏毒性。因此，我们研究了不同的胶束形成生物材料，如 Soluplus、Pluronic F127、Tetronic T1107 和 d-α-生育酚聚乙二醇 1000 琥珀酸酯（TPGS），以开发用于 DOX 递送的潜在混合胶束纳米载体。由于 DOX 盐酸盐是一种封装在混合胶束疏水性核内的不良候选物，我们检测了 DOX 与脱氧胆酸钠（NaDC）之间的疏水性复合物，作为一种封装在聚合物胶束内的候选物。T1107：TPGS（1:3，重量比）的组合表现出最佳的物理化学性质和高 DL 能力（6.43%w/v）。特别是，DOX 的体外释放率在酸性肿瘤微环境 pH 值（5.5）下高于生理对照 pH 值（7.4）。载 DOX/NaDC 的混合胶束系统的水动力学直径为 10.7nm（PDI=0.239）。混合胶束制剂的体外细胞毒性显著（p<0.05）高于 Doxil 对卵巢（SKOV-3）和三阴性乳腺癌细胞（MDA-MB-231）的细胞毒性。此外，细胞摄取实验表明，与 Doxil 相比，混合胶束对 SKOV-3（孵育 2、4 和 6h）和 MDA-MB-231（孵育 4h）细胞的 DOX 细胞内含量均有显著增加（p<0.05）。这些发现表明，T1107：TPGS（1:3）混合胶束可用作 DOX 药物递送的潜在纳米技术平台。
