Title:Role of Generation, Architecture, pH and Ionic Strength on Successful siRNA Delivery and Transfection by Hybrid PPV-PAMAM Dendrimers
VOLUME: 19 ISSUE: 29
Author(s):G. M. Pavan, S. Monteagudo, J. Guerra, B. Carrion, V. Ocana, J. Rodriguez-Lopez, A. Danani, F. C. Perez-Martinez and V. Cena
Affiliation:Unidad Asociada Neurodeath, Facultad de Medicina, Avda. Almansa, 14, 02006 Albacete Spain.
Keywords:Dendrimer, pH, ionic strength, siRNA transfection, molecular dynamic simulation
Abstract: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.
