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.
Highlights
Polyamidoamine (PAMAM) dendrimers represent a class of hyperbranched polymers that are versatile vehicle candidates in nanomedicine, especially in the fields of diagnosis and cancer therapy[4]
The present study modelled the amphiphilic dendrimers (ADs) systems introduced by Yu et al.[16] to deepen understandings on micelle formation and small-interfering RNA (siRNA) binding, as well as to explain the successful results of generation 2 (G2)-18C ADs as gene vectors
To characterize the events driving self-assembly of this class of amphiphilic dendrimers, the fusion of two aggregates from the G2-18C system was considered as a case-of-study to verify if these systems are acting as typical ionic surfactants (Fig. 3a)
Summary
The simulations were carried out using the GROMACS package (version 5.0.3)[32]. The method of steepest descent was employed for energy minimization using a force tolerance of 10 kJ mol−1 nm−1. Khalid and Corsi et al.[36,37] developed a CG DNA model based on MARTINI CG beads, using one bead for phosphate groups, two for deoxyribose sugars, and two or three beads depending on the base types. Bonding interactions of DNA were treated using an elastic network approach, where all particles separated by distances up to 0.7 nm were restrained with a harmonic potential of 1500 kJ mol−1 nm[2]. The equilibrium bond-lengths were taken from a B-form of DNA and validated by Khalid and Corsi et al.[36,37] using several full-atom MD simulations in water and counterions. Based on Khalid and Corsi et al.[36,37], the same bead types were employed for phosphate groups, as well as for guanine, cytosine, and adenine.
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