pH-stimuli-responsive doxorubicin release and stability in chitosan–Eudragit nanocarriers

The efficacy of pH-responsive nanocarriers in targeted cancer therapy hinges on their stability in circulation (pH 7.4) and controlled drug release in the acidic tumor microenvironment (pH ~ 5-6.5). This study elucidates the molecular mechanism of doxorubicin (DOX) interaction with and release from chitosan–Eudragit nanocarriers using integrated all-atom (AA-MD) and coarse-grained (CG-MD) molecular dynamics simulations. Our simulations reveal a stark contrast in behavior between neutral (pH 7) and acidic (pH 5) conditions. At pH 7, the system exhibits remarkable stability, characterized by a lower average RMSD (5.25 nm vs. 5.84 nm at pH 5) and significantly stronger drug-carrier binding. This is evidenced by an approximately three-fold larger drug-nanocarrier contact surface area and a > 50% higher number of stabilizing hydrogen bonds compared to acidic conditions. The protonation of ionizable groups at pH 5 induces electrostatic repulsion, leading to nanocarrier deformation, a drastic reduction in interactions, and ultimately, DOX release. The consistency of these findings across both AA-MD and CG-MD simulations validates the robustness of our models. This work provides a fundamental molecular-level understanding of the pH-responsive behavior of chitosan–Eudragit carriers, confirming their high potential for targeted DOX delivery and establishing a computational framework for the rational design of next-generation smart nanocarriers.