Complexation of siRNA with Galactose-Functionalized Dendrimers: PAMAM vs PETIM

siRNA-based therapies show potential for treating various diseases, but achieving efficient and targeted delivery remains a challenge. In this study, we investigated the potential of galactose-functionalized poly(amidoamine) (Gal-PAMAM) and poly(propyl ether imine) (Gal-PETIM) dendrimers as carriers for gene delivery, specifically, small interfering RNA (siRNA), using all-atom molecular dynamics simulations. We demonstrated the complexation behavior for both systems at two distinct pH conditions, i.e., 7 and 10, by analyzing the 500 ns long trajectories. The results show that electrostatic interactions are crucial for complex formation, with PMF profiles (center-of-mass, i.e., COM distance, was used as a reaction coordinate to calculate the potential of mean force, i.e., PMF) indicating a stronger binding affinity for Gal-PAMAM/siRNA at pH 7. In the Gal-PAMAM/siRNA complex at pH 7, the siRNA shows higher structural fluctuations compared with the Gal-PETIM/siRNA complex. However, in polar solvents, Gal-PETIM exhibits hydrophobic behavior, enabling rapid gene delivery at physiological pH conditions. These findings indicate that Gal-PETIM dendrimers are promising for effective siRNA delivery at physiological pH. This is due to their superior stability in forming complexes, strong interaction capabilities, and ability to rapidly release genes. Our results significantly improve the understanding of the applications of galactose-functionalized dendrimers under two different pH conditions.