Methotrexate Complexation with Native and PEGylated PAMAM‐G4: Effect of the PEGylation Degree on the Drug Loading Capacity and Release Kinetics

Native and PEGylated poly‐amidoamine‐G4 (PAMAM‐G4) dendrimers with PEGylation degrees of 0%, 28%, 34%, 67%, and 100% are evaluated as potential drug carriers for methotrexate (MTX). A maximum complex stoichiometry of 47:1 is obtained for the system with 34% of PEGylation, with an estimated binding constant of 1.2 × 104 mol−1 per binding site, as derived from aqueous solubility profiles. 2D‐NOESY experiments reveal a preferential complexation of MTX within PAMAM‐G4 branches, suggesting that high PEGylation ratios restrict drug diffusion toward innermost PAMAM cavities. On the other hand, high PEGylation degrees considerably decrease the rate of MTX release, which can be attributed to a reduced dendrimer swelling due to surface polyethylene glycol crowding. All release profiles follow first‐order kinetics, suggesting a diffusion‐controlled mechanism for MTX release. These results can be helpful to understand the molecular basis underlying the complexation and release of MTX with PEGylated PAMAM dendrimers aimed at designing more efficient drug delivery systems.