(206e) Pegylated PAMAM Dendrimer Nanocarriers: A Microscopic View From Atomistic Computer Simulations

Poly(amido-amine) (PAMAM) dendrimers are very promising nanocarriers in a wide range of biomedical applications, including gene and drug delivery, and as imaging agents.  They have a unique structure, which is characterized by high size uniformity, low polydispersity, and a large number of modifiable surface groups.  Dendrimer nanocarriers (DNCs) are usually further modified through the conjugation of ligands in order to confer specific characteristics to the carriers, so as to enhance their efficacy, as for example in cellular and organelle targeting.  The chemistry and structure of the solvated ligand-conjugated DNCs will dictate how they interact with the physiological environment, and, therefore, their behavior and function.  Understanding the microstructures of ligand-conjugated DNC is, therefore, of great relevance within the context of drug delivery applications.

In this work we investigated the effect of poly(ethylene glycol) (PEG) molecular weight (Mw – 500 vs. 1000) and grafting density (no, low, medium and high) on the microstructure of NH₂-terminated PAMAM DNCs through fully atomistic molecular dynamics (MD) simulations.  We start by analyzing the effect of generation (G) of the DNCs’ on their solvated microstructure, from G2 to G5 (G2NH₂-G5NH₂).  The results obtained showed a very good agreement with available experimental measurements from SANS and SAXS.  No back-folding is observed for PAMAM dendrimers with generation lower than G5NH₂.  G2NH₂ and G3NH₂ showed a dense-packed, non-globular structure while G4NH₂ and G5NH₂ have a segmented, “open” structure.  PEGylation has two competing effects on dendrimer core size: one is to expand the core of the dendrimers because of PEG solvation, while the other is to shrink the dendrimer core size because every PEG chain grafted will consume one charged primary amine, thus resulting in decreased electrostatic repulsion.  It was also observed that grafting shorter PEG chains at higher densities exerted similar swelling of the dendrimer core as grafting longer PEG chains at smaller densities.  Oxygen from PEG is seen to have strong interactions with the primary amine from dendrimers, and this lead to a collapsed PEG structure, which is very relevant to the function of PEGylated DNCs as it impacts its hydrated size, further chemistry (conjugation), and the release of therapeutics.  These effects are explored in detail in this work.