Graphene oxide-chitosan nanocomposites for phenethyl isothiocyanate delivery in glioma

Abstract

Hydrophobic drug delivery remains a major challenge in nanomedicine due to poor aqueous solubility, weak carrier–drug interactions, and uncontrolled in vivo distribution. Phenethyl isothiocyanate (PEITC), a hydrophobic anticancer agent currently under clinical investigation, exhibits low bioavailability and off-target toxicity, necessitating improved carrier strategies. Previous studies have explored graphene oxide-based formulations (GO–PEITC) for PEITC delivery; however, the role of chitosan-modified graphene oxide in regulating PEITC behavior through interfacial interactions has not been systematically examined. In this work, we utilize a covalently assembled graphene oxide–chitosan (GOCS) nanocomposite formed through amide coupling to enable controlled interfacial interactions with PEITC that govern its intracellular availability and bioactivity. PEITC interacts strongly with the GOCS matrix through a combination of electrostatic attraction, hydrogen bonding, and π–π interactions, resulting in efficient molecular retention and protection within the nanocomposite structure. Compared with unmodified graphene oxide, chitosan-functionalized graphene oxide acts as an active interfacial regulator, modulating surface charge, colloidal stability, and interlayer interactions to promote cooperative π–π stacking and polymer-mediated confinement of PEITC, leading to a stabilized GOCS–PEITC nanocomposite with enhanced drug-loading efficiency and pH-responsive release under acidic tumor-mimicking conditions. As a result, GOCS–PEITC exhibits improved intracellular delivery, induces β-tubulin destabilization, γ-H2AX-expression, apoptosis, and broad proteomic pathway modulation, and achieves superior tumor growth inhibition with favorable systemic biocompatibility in a subcutaneous glioma model.