Balanced Adsorption and Acidic-Condition Interfacial Reorganization of Anticancer Drugs on Doped ZnO Nanocarrier Interfaces

Abstract Adsorption-mediated nanocarriers require a balance between stable drug loading and sufficient interfacial responsiveness under acidic biological conditions. Here, we present a Sabatier-guided computational workflow to examine the interfacial adsorption and acidic-condition response of six anticancer drugs, namely 5-fluorouracil, capecitabine, cyclophosphamide, gemcitabine, methotrexate, and paclitaxel, on doped ZnO nanocarrier interfaces. Mg-, Ca-, Na-, K-, and N-substituted ZnO models were evaluated using DFTB/COSMO/D3 calculations. Native nonprotonated adsorption was first used to construct drug-specific Sabatier windows and to select balanced-loading and weak-edge candidates. Selected monoprotonated (H1) and diprotonated (H2) microstates were then used as operational protonation challenges, motivated by mildly and more strongly acidic biological environments rather than interpreted as pKa-weighted physical pH states, and were analyzed using geometry-based descriptors, including center-of-mass displacement, final cation–heteroatom contact distance, Zn···O/Zn···N contacts, and anchor switching. The results show that balanced-loading candidates generally retain stable interfacial contact after acidic perturbation, whereas weak-edge candidates are more susceptible to anchor switching, interfacial reorientation, and interface weakening. Desorption-like optimized geometries are observed only for selected 5-fluorouracil microstates on K-substituted ZnO, while larger drugs mainly preserve surface association through alternative O/N anchoring groups. These findings provide a conservative interface-design strategy for distinguishing stable loading, acidic-condition reorganization, weakened interfaces, and desorption-like final geometries on doped ZnO nanocarrier interfaces.