Surface Functionality and pH Govern Structural Dynamics and Drug Binding in PETIM and PAMAM Dendrimers

Surface functionality and pH significantly influence the structural dynamics, hydration, and drug-binding capabilities of PAMAM and PETIM dendrimers. To explore this phenomenon, all-atom molecular dynamics simulations were conducted on diverse generations of both dendrimer types, each with distinct core architectures and terminal group modifications.

The tertiary branch-point amines, upon protonation, exhibit expanded structures and increased porosity, consequently boosting structural fluctuations. Conversely, non-protonated amine and carboxylic acid terminations result in more compact dendrimer conformations. Sugar-functionalized dendrimers, such as those terminated with beta-galactose for PETIM and D-glucose for PAMAM, display enhanced hydration levels and rigidity. However, amine-terminated dendrimers reveal the most pronounced conformational dynamics.

PAMAM dendrimers with -NH2, -NH3+, and -COO- terminal groups tend to be more hydrated than their PETIM counterparts, while beta-galactose-terminated PETIM dendrimers are comparatively more hydrophilic than D-glucose-terminated PAMAM dendrimers. Furthermore, N-core PETIM dendrimers tend to exhibit more spherical shapes compared to their O-core equivalents.

Drug-binding simulations suggest that curcumin interacts primarily via van der Waals forces, while doxorubicin binding is primarily driven by electrostatic interactions. Among the surface functionalities assessed, -NH2, -NH3+, -COOH, and -COO-(DeP) terminations demonstrate the most favorable drug-binding attributes. With the exception of deprotonated carboxylate systems, curcumin exhibits stronger binding affinity over doxorubicin.

These results collectively elucidate the intricate molecular relationships between surface functionality, protonation state, dendrimer architecture, and drug-binding behavior. This understanding paves the way for designing pH-responsive dendrimer nanocarriers with improved drug-loading and controlled-release capabilities.