Effects of PEGylation on the Size and Internal Structure of Dendrimers: Self-Penetration of Long PEG Chains into the Dendrimer Core

Abstract

G4 PAMAM dendrimers grafted with poly(ethylene glycol) (PEG) of different sizes (M w = 550 and 5000) and grafting densities (12−94% of surface terminals) were simulated using the coarse-grained (CG) force fields previously developed and reparametrized in this work. Simulations are carried out for G4, G5, and G7 un-PEGylated dendrimers that are either unprotonated, terminally protonated, or protonated on both terminals and interior sites, corresponding to pH values of >10, 7, and <5, respectively. As protonation increases, simulations show only a small (∼6% for G4 and G5) change of dendrimer radius of gyration R g and show a structural transition from dense-core to dense-shell structure, both of which are in agreement with recent scattering experiments and all-atom simulations. For the PEGylated dendrimers, the R g of the fully PEG(M w = 5000)-grafted dendrimer also agrees well with experiment. Longer PEG chains with higher grafting density yield PEG−PEG crowding, which stretches dendrimer terminals toward water more strongly, leading to larger size and a dense-shell structure of the dendrimer. Long PEG chains at high grafting densities also penetrate into the dendrimer core, while short ones do not, which might help explain the reduced encapsulation of hydrophobic compounds seen experimentally in dendrimers that are 75%-grafted with long PEG’s (M w = 5000). This reduced encapsulation for dendrimers with long grafted PEG’s has previously been attributed to PEG-induced dendrimer aggregation, but this explanation is not consistent with our previous simulations which showed no aggregation even with long PEG’s but is consistent with the new simulations reported here that show PEG penetration into the core of the dendrimer to which the PEG is attached.

Conjugation of polybasic dendrimers with neutral grafts: effect on conformation and encapsulation of acidic drugs

“…Consistent with above changes in the dendrimer density profiles, the density of grafted monomers near the core of the dendrimer is seen to decrease while the tail of its density profile increases with N G . These trends also agree with the previous simulations, 32,35 and are again attributed to the increased tension along the backbone of the grafts, which increases with N G .…”

“…In their studies, they accurately reproduced experimentally measured sizes of PEGylated dendrimers, and observed brushlike behavior of the dendrimer grafts at high grafting densities. [34][35][36] In this work, we report the results of coarse-grained modeling of the influence of neutral grafts upon the conformations of polyelectrolyte dendrimers and their subsequent influence on the complexation between weakly acidic drug molecules and polybasic dendrimers. The present work was motivated by our recent article which developed a self-consistent field theory (SCFT) model to study the complexation between weakly basic nongrafted dendrimers and weakly acidic drug molecules.…”

Simulating the interaction of lipid membranes with polymer and ligand-coated nanoparticles

“…It is known from experiments that PEGylation is more effective than acetylation at reducing nonspecific binding of dendrimers to membranes, making PAMAM dendrimers more biocompatible. Simulations confirmed that PEGylation reduces pore formation by screening dendrimer charges, preventing direct interaction with lipid head groups and with other dendrimers, hindering aggregation [84].…”

“…The same authors also investigated the effect of dendrimer PEGylation (i.e. attaching polyethylene glycol -PEG -to the dendrimer surface) on their interaction with membranes [84]. It is known from experiments that PEGylation is more effective than acetylation at reducing nonspecific binding of dendrimers to membranes, making PAMAM dendrimers more biocompatible.…”

Molecular Modeling of PEGylated Peptides, Dendrimers, and Single-Walled Carbon Nanotubes for Biomedical Applications

“…Our group performed CG MD simulations of PEGylated dendrimers, showing the inhibition effect of PEG chains on the interparticle aggregation in water [131] and on the dendrimer-induced pore formation in lipid bilayers [132]. In particular, we simulated generations 3, 4, and 5 dendrimers grafted with PEGs of different sizes (M w = 550 and 5000) and grafting densities (12%-94% of surface terminals), showing that longer PEG chains with higher grafting density yield PEG-PEG crowding, which stretches dendrimer terminals towards water, leading to a larger size and a dense-shell structure of the dendrimer [133], as shown in Figure 5. Also, simulations showed that long PEG5000 chains at high grafting density self-penetrate into the attached dendrimer, occupying the dendrimer's vacant interior that would otherwise be available for encapsulating hydrophobic compounds, implying that the encapsulation efficiency of dendrimers can be modulated by the PEG length and grafting density.…”