(227m) The Chemistry of the Terminal Surface Groups of PAMAM Dendrimers Determine the Microstructure of the Grafted Peg Layer

Poly(amido amine) (PAMAM) dendrimers are promising nanocarriers in a wide range of biomedical applications including gene and drug delivery and as imaging agents.  PAMAM dendrimers are characterized by high size uniformity, low polydispersity and multifunctional surface groups that are readily modifiable.  Poly (ethylene glycol) (PEG) is a versatile ligand and widely used to modify polymeric nanocarriers.  PEGylation of PAMAM dendrimer nanocarriers (DNC) can increase the aqueous solubility of the nanocarriers when hydrophobic therapeutics are conjugated, it helps protect the conjugated payload, improves biocompatibility of the DNCs, can function as a linker to better present targeting ligands, and helps modulate extra- and intra-cellular transport.  The microstructure of the PEG layer grafted onto PAMAM dendrimers will impact how the DNCs interact with the physiological environment, and therefore, the therapeutic efficacy of the drug molecules.  Understanding the microstructure of PEGylated PAMAM dendrimers is, thus, of great relevance in the context of drug / gene delivery applications.

In this work, molecular dynamic (MD) simulations were employed to investigate the effect of the chemistry of the terminal surface groups of PAMAM on the microstructure of the PEG graft layer.  Generation 3 (or 2.5) PAMAM dendrimers with amine (G3NH2), hydroxyl (G3OH) and carboxyl (G2.5COOH) surface groups were selected for this study to represent cationic (G3NH3⁺), neutral (G3OH) and anionic (G2.5COO^-) dendrimers – state of the dendrimers under physiological conditions.  All dendrimers were PEGylated with 8 units of PEG, with 1000Da (PEG1000).  We observed that G3NH3⁺ and G2.5COO^- assume a significantly more “open” structure compared to G3OH.  The chemistry of the terminal surface group was seen to greatly impact the structure of the grafted PEG layer.  The PEG layer grafted onto G3NH3+ is fairly collapsed due to strong interaction with the ether groups.  Conversely the COO^- groups in the anionic dendrimer tend to help expand the PEG graft layer.  These qualitative results are related to quantitative properties of the microstructure such as radial distribution functions.  These results are relevant as they allow us to guide the design of DNCs and their conjugates for drug delivery applications.