Coarse-Grained Molecular Dynamics Simulations of the Self-Assembly of Amphiphilic Dendrimers as Gene Carriers

Abstract

The development of safe and effective liberation mechanisms is the most important requirements for the clinical implementation of drug-delivery vectors. Among non-viral delivery systems, the most popular ones are members of the groups of cationic lipids and polymers. Both subgroups are able to transport nucleic acids, protect them against environmental influences and deliver them to the cells. Without a doubt, these systems bear certain disadvantages as well, among these, high toxicities for in vitro/in vivo applications in the case of liposomes and an almost infinite inherent structural complexity for polymers. From this point of view, an ideal transfection system would combine the characteristic advantages of cationic lipids and polymers, while at the same time minimizing their limitations. Recently, a hybrid structure consisting of a lipid and a spherical polymer (dendrimer) was reported, which was consequently named amphiphilic dendrimer (AD). Gratifyingly, these molecules have shown both excellent delivery properties and payload-liberation as well as low toxicity, mainly due to their chimeric structure, bearing a hydrophobic alkylic chain and a hydrophilic dendron as head group.To gain insight into these nanoparticles we studied them using a molecular simulation approach. Specifically, we studied the structural properties that govern the self-assembly organization and how these complexes interact with DNA. Since the computational cost for this kind of studies at atomic level are very high, a coarse-grained approach was used. All the calculations were performed using Martini force-field. Using this approach, a large number of dendrimeric systems were studied using large-scale molecular simulation, which allow us to explore a large number of configurational and conformational states of the self-assembly process, obtaining significant statistical results.