Department of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou.
Department of Pharmacy, School of Medicine Science, Jiaxing University, Jiaxing.
Int J Nanomedicine. 2016 Dec 12;11:6713-6725. doi: 10.2147/IJN.S111647. eCollection 2016.
One of the major obstacles in the treatment of breast cancer is breast cancer stem cells (BCSC) which are resistant to standard chemotherapeutic drugs. It has been proven that microRNA-200c (miR-200c) can restore sensitivity to microtubule-targeting chemotherapeutic drugs by reducing the expression of class III β-tubulin. In this study, combination therapy with miR-200c and paclitaxel (PTX) mediated by lipid nanoparticles was investigated as an alternative strategy against BCSC.
A cationic lipid 1,2-dioleoyl-3-trimethylammonium-propane was strategically selected to formulate solid lipid nanoparticles (SLN) for miR-200c delivery. Nanostructured lipid carriers (NLC) with 20 wt% oleic acid were prepared for PTX delivery. Mammospheres, which gained the characteristics of BCSC, were used as a cell model to evaluate the efficiency of combination therapy.
The cationic SLN could condense anionic miRNA to form SLN/miRNA complexes via charge interactions and could protect miRNA from degradation by ribonuclease. SLN/miR-200c complexes achieved 11.6-fold expression of miR-200c after incubation for 24 hours, compared with that of Lipofectamine™ 2000/miR-200c complexes (*<0.05). Intracellular drug release assay proved that miRNA can be released from SLN/miRNA complexes efficiently in 12 hours after cellular uptake. After BCSC were transfected with SLN/miR-200c, the expression of class III β-tubulin was effectively downregulated and the cellular cytotoxicity of PTX-loaded NLC (NLC/PTX) against BCSC was enhanced significantly (**<0.01).
The results indicated that the cationic SLN could serve as a promising carrier for miRNA delivery. In addition, the combination therapy of miR-200c and PTX revealed a novel therapeutic strategy for the treatment of BCSC.
乳腺癌治疗的主要障碍之一是乳腺癌干细胞（BCSC），其对标准化疗药物具有抗性。已经证明，microRNA-200c（miR-200c）可以通过降低 III 类β-微管蛋白的表达来恢复对微管靶向化疗药物的敏感性。在这项研究中，通过脂质纳米粒研究了 miR-200c 与紫杉醇（PTX）的联合治疗，作为针对 BCSC 的替代策略。
选择阳离子脂质 1,2-二油酰基-3-三甲铵丙烷（DOTAP）来构建用于 miR-200c 递送的固体脂质纳米粒（SLN）。制备了载有 20wt%油酸的纳米结构脂质载体（NLC）用于 PTX 递送。类乳腺球体（获得 BCSC 特征的球体）被用作细胞模型来评估联合治疗的效率。
阳离子 SLN 可以通过电荷相互作用使带负电荷的 miRNA 凝聚形成 SLN/miRNA 复合物，并可以防止 miRNA 被核糖核酸酶降解。与 LipofectamineTM2000/miR-200c 复合物相比（*<0.05），孵育 24 小时后，SLN/miR-200c 复合物中的 miR-200c 表达增加了 11.6 倍。细胞内药物释放实验证明，miRNA 可以在细胞摄取后 12 小时内从 SLN/miRNA 复合物中有效释放。BCSC 经 SLN/miR-200c 转染后，III 类β-微管蛋白的表达被有效下调，载有 PTX 的 NLC（NLC/PTX）对 BCSC 的细胞毒性显著增强（**<0.01）。
结果表明，阳离子 SLN 可以作为 miRNA 递送的有前途的载体。此外，miR-200c 和 PTX 的联合治疗为治疗 BCSC 提供了一种新的治疗策略。
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