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
Yoosefian et al. (Sun,) studied this question.