Anthracene-driven π-π stacking assembly of disulfide prodrug nanoparticles for enhanced chemotherapy safety

Despite advances in cancer therapy, chemotherapy limitations like off-target toxicity persist. Prodrug-based self-assembled nanodelivery systems offer a promising strategy to overcome these constraints. This study introduces anthracene (An) as a novel modification module leveraging π-π stacking to engineer disulfide-bridged docetaxel (DTX) prodrug nanomedicines (An-SS-DTX NPs). Three prodrugs (α-, β-, γ-An-SS-DTX) were synthesized, differing in alkyl linker length adjacent to the disulfide bond. Optimized nanoparticles (50-80 nm) formed via nanoprecipitation with 20 % DSPE-PEG2000 exhibited excellent colloidal and physiological stability. Mechanistic studies revealed nanoparticle assembly is driven by a dual mechanism: robust hydrophobic interactions and directional π-π stacking between An moieties - identified as the principal driving force via force-specific competitors, fluorescence quenching, and molecular simulations. Crucially, functioning as a modification module, An significantly modulates redox-triggered disulfide cleavage. Remarkably, DTX remains unreleased even in H₂O₂, unveiling unprecedented insights into disulfide prodrug release. Moreover, the An moiety as a modification module plays a significant role in affecting the pharmacokinetic properties of nanoparticles, particularly for γ-An-SS-DTX NPs, which showed a 16.6-fold higher AUC than free DTX. In a 4T1 xenograft model, all An-SS-DTX NPs achieved tumor suppression equivalent to the clinical formulation Taxotere®. Morever, they exhibited markedly reduced systemic toxicity, significantly mitigating Taxotere®-associated hepatorenal injury and hemorrhagic cardiotoxicity. This work establishes An based π-π stacking as a robust strategy to drive the self-assembly of reduction-selective disulfide prodrug nanoparticles, balancing potent antitumor efficacy with enhanced safety profiles, and provides a theoretical basis for constructing disulfide-based nanodelivery systems driven by π-π interactions.