University of Applied Sciences of Southern Switzerland (SUPSI)-Laboratory of Applied Mathematics and Physics (LaMFI). Manno, Switzerland.
Curr Med Chem. 2012;19(29):4929-41. doi: 10.2174/0929867311209024929.
Small interfering RNA (siRNA) constitutes an excellent way of knocking down genes. However, it requires the use of delivery systems to reach the target cells, especially to neuronal cells. Dendrimers are one of the most widely used synthetic nanocarriers for siRNA delivery. However, due to the complexity of the dendrimer-siRNA interactions, when a new dendritic carrier is designed it is difficult to predict its efficiency to bind and to deliver siRNA. At the same time it is not easy to understand the origin of eventual limited functionalities. We have modeled the interactions between two dendrimers (TDG-G1 and TDG-G2) and siRNA using molecular dynamics (MD) simulation. The results were compared to experimental physico-chemical parameters such as siRNA complexation, complex stability, size, and zeta potentials and biological effects such as down-regulation of a specific RNA expression in cortical neurons in culture. Data indicate that the combination of rigid core and flexible branches guarantees strong siRNA binding, which is important to have a good transfection profile. However, the successful nanocarrier for siRNA delivery (TDG-G1) is identified not only by a high affinity for siRNA, but by a favorable equilibrium between a strong binding and the ability to release siRNA to exert its biological action. The conditions under which the dendriplex is formed are also relevant for transfection efficiency and biological activity.
小干扰 RNA（siRNA）是一种有效的基因敲低方法。然而，它需要使用输送系统来达到靶细胞，特别是神经元细胞。树突状聚合物是用于 siRNA 输送的最广泛使用的合成纳米载体之一。然而，由于树突状聚合物-siRNA 相互作用的复杂性，当设计新的树突状载体时，很难预测其结合和输送 siRNA 的效率。同时，也不容易理解最终有限功能的起源。我们使用分子动力学（MD）模拟研究了两种树突状聚合物（TDG-G1 和 TDG-G2）和 siRNA 之间的相互作用。将结果与实验物理化学参数（如 siRNA 复合物形成、复合物稳定性、大小和 ζ 电位）和生物效应（如培养的皮质神经元中特定 RNA 表达的下调）进行了比较。数据表明，刚性核心和柔性支链的结合保证了 siRNA 的强结合，这对于具有良好转染谱的载体是很重要的。然而，成功的 siRNA 输送纳米载体（TDG-G1）不仅通过与 siRNA 的高亲和力来识别，还通过强结合与释放 siRNA 以发挥其生物作用之间的有利平衡来识别。形成树突状聚合物的条件也与转染效率和生物活性有关。
