Self-Assembly of Amphiphilic Dendrimers: The Role of Generation and Alkyl Chain Length in siRNA Interaction

Abstract

An ideal nucleic-acid transfection system should combine the physical and chemical characteristics of cationic lipids and linear polymers to decrease cytotoxicity and uptake limitations. Previous research described new types of carriers termed amphiphilic dendrimers (ADs), which are based on polyamidoamine dendrimers (PAMAM). These ADs display the cell membrane affinity advantage of lipids and preserve the high affinity for DNA possessed by cationic dendrimers. These lipid/dendrimer hybrids consist of a low-generation, hydrophilic dendron (G2, G1, or G0) bonded to a hydrophobic tail. The G2-18C AD was reported to be an efficient siRNA vector with significant gene silencing. However, shorter tail ADs (G2-15C and G2-13C) and lower generation (G0 and G1) dendrimers failed as transfection carriers. To date, the self-assembly phenomenon of this class of amphiphilic dendrimers has not been molecularly explored using molecular simulation methods. To gain insight into these systems, the present study used coarse-grained molecular dynamics simulations to describe how ADs are able to self-assemble into an aggregate, and, specifically, how tail length and generation play a key role in this event. Finally, explanations are given for the better efficiency of G2/18-C as gene carrier in terms of binding of siRNA. This knowledge could be relevant for the design of novel, safer ADs with well-optimized affinity for siRNA.

Self-Assembly Behavior of Amphiphilic Janus Dendrimers in Water: A Combined Experimental and Coarse-Grained Molecular Dynamics Simulation Approach

“…On the other hand, the authors describe the formation of vesicles from higher generation JDs (hydrophobic-hydrophilic block generations: G2-G3 and G3-G3). According to this result and previous studies of CG-MD focused on the self-assembly of different generation amphiphilic dendrimers [ 15 ], generation of the hydrophilic block influences the morphology of the assemblies and higher dendrimer generation could derive in the formation of vesicles. One limitation of our study is that we do not evaluate different concentrations or compositions of dendrimers in the simulation, to explore other assemblies’ morphologies.…”

“…The geometrical condition in the molecular structure of the amphiphiles to form that edges in micelles is that their packing parameter factor accomplish v / a o l c < 1/3, where v is the volume of their hydrocarbon chains, a o is their optimal area per head group that minimize the free energy and l c is roughly the length of the hydrocarbon chain [ 32 ]. According to this, the volume of the JDs hydrocarbon chains is too high compared to the polar head group area, causing that they cannot form micelles, in contrast to single-tailed amphiphilic dendrimers, such as PAMAM-G2 derivatives [ 15 ].…”

“…Interdigitation degree in bilayers is related to the size, hardness, and stability of aggregates [ 9 ]. This parameter is influenced by the length of hydrophobic tails [ 15 ] and other factors, such as the formation of hydrogen bonds between the hydrophilic segments of the membrane dendrimers, which prevent the interdigitation [ 11 ]. The dendrimer studied here is composed of bis-MPA moieties with hydroxyl groups that form this type of interactions and may be influencing the arrangement of the dendrimers in the bilayers.…”

“…CG modeling consists of the simplification of molecular structure by mapping several atoms as single interactions sites reducing the number of degrees of freedom and maintaining the essential molecular features [ 13 , 14 ]. CG-MD simulation has already been applied to Percec-type JDs that formed dendrimersomes [ 3 ] and to other amphiphilic dendrimers [ 15 ].…”

Integration of target discovery, drug discovery and drug delivery: A review on computational strategies

“…MARTINI method was employed by Márquez‐Miranda et al to investigate the self‐assembly of amphiphilic PAMAM G2 dendrimers. This study demonstrated that those dendrimers can assemble into regular micelles, and that depending on the generation and amphiphilic tail length of them, their ability to bind a small‐interfering RNA (Márquez‐Miranda et al, ). Such an approach can be also considered for the study of other classes of nanoparticles.…”