Molecular Dynamics Study of pH-Responsive PAMAM Dendrimer–Topotecan Complex: loading Mechanism, Membrane Transport, and Release Mechanism

The clinical efficacy of topotecan (TPT) is limited by its instability and rapid clearance, motivating the search for nanoscale carriers capable of enhancing its delivery. Polyamidoamine (PAMAM) dendrimers offer a promising platform; however, the molecular-level mechanisms governing TPT loading, membrane transport, and pH-triggered release remain insufficiently understood. In this work, atomistic molecular dynamics simulations were employed to elucidate the encapsulation of TPT within a G4 PAMAM dendrimer, the translocation of the resulting complex across a DPPC lipid bilayer, and its release under acidic conditions. The dendrimer stably accommodated multiple TPT molecules through strong van der Waals and hydrogen-bonding interactions. The TPT@PAMAM complex successfully penetrated the lipid membrane, exhibiting a well-defined translocation pathway. Under acidic pH, protonation-induced electrostatic repulsion facilitated efficient drug release from the dendrimer. These findings provide atomistic insights into the pH-responsive behavior of PAMAM nanocarriers and support their potential for enhancing the targeted delivery of topotecan in cancer therapy. • MD analysis of TOPOTECAN loading into PAMAM dendrimers at neutral pH • Efficient membrane translocation of TOPOTECAN@PAMAM across DPPC bilayer • pH-triggered release of TOPOTECAN from protonated PAMAM dendrimers • Strong vdW and H-bond interactions stabilize TOPOTECAN loading • Acidic conditions enhance drug release via electrostatic repulsion