Hefei National Laboratory for Physical Sciences at Microscale and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230027, P.R. China.
ACS Nano. 2011 Feb 22;5(2):1483-94. doi: 10.1021/nn103349h. Epub 2011 Jan 4.
Combination of two or more therapeutic strategies with different mechanisms can cooperatively prohibit cancer development. Combination of chemotherapy and small interfering RNA (siRNA)-based therapy represents an example of this approach. Hypothesizing that the chemotherapeutic drug and the siRNA should be simultaneously delivered to the same tumoral cell to exert their synergistic effect, the development of delivery systems that can efficiently encapsulate two drugs and successfully deliver payloads to targeted sites via systemic administration has proven to be challenging. Here, we demonstrate an innovative "two-in-one" micelleplex approach based on micellar nanoparticles of a biodegradable triblock copolymer poly(ethylene glycol)-b-poly(ε-caprolactone)-b-poly(2-aminoethyl ethylene phosphate) to systemically deliver the siRNA and chemotherapeutic drug. We show clear evidence that the micelleplex is capable of delivering siRNA and paclitaxel simultaneously to the same tumoral cells both in vitro and in vivo. We further demonstrate that systemic administration of the micelleplex carrying polo-like kinase 1 (Plk1) specific siRNA and paclitaxel can induce a synergistic tumor suppression effect in the MDA-MB-435s xenograft murine model, requiring a thousand-fold less paclitaxel than needed for paclitaxel monotherapy delivered by the micelleplex and without activation of the innate immune response or generation of carrier-associated toxicity.
两种或多种作用机制不同的治疗策略联合应用可以协同抑制癌症的发展。化疗和基于小干扰 RNA（siRNA）的治疗相结合就是这种方法的一个例子。假设化疗药物和 siRNA 应该同时递送到同一肿瘤细胞中以发挥协同作用，开发能够有效包裹两种药物并通过系统给药将有效载荷递送到靶向部位的递药系统已被证明具有挑战性。在这里，我们展示了一种基于两亲性嵌段共聚物聚（乙二醇）-b-聚（ε-己内酯）-b-聚（2-氨基乙基乙烯基磷酸酯）的可生物降解的胶束纳米粒的创新“二合一”胶束复合物方法，用于系统递送 siRNA 和化疗药物。我们清楚地证明了胶束复合物能够在体外和体内将 siRNA 和紫杉醇同时递送到相同的肿瘤细胞。我们进一步证明，携带 Polo 样激酶 1（Plk1）特异性 siRNA 和紫杉醇的胶束复合物的系统给药可以在 MDA-MB-435s 异种移植小鼠模型中诱导协同的肿瘤抑制作用，所需的紫杉醇量比胶束复合物递送紫杉醇单药治疗所需的紫杉醇量少一千倍，且不会激活固有免疫反应或产生载体相关毒性。
