Fabrication of a hyaluronic acid-targeted supramolecular delivery platform with multi-mode drug release

A supramolecular drug delivery system was fabricated in this study based on the assembly of β-cyclodextrin grafted hyaluronic acid and disulfide bridged ferrocene with thermally sensitive polymeric p(AAm-co-AN). The system demonstrates effective encapsulation capability for hydrophobic antitumor drugs (DOX, PTX, and α-TOS) with high loading levels. However, only DOX's release kinetics and therapeutic efficacy were comprehensively characterized in this study. The DOX loaded nanoparticles can achieve effective cancer targeting and endocytosis with HA components serving as hydrophilic nanoparticle outer shells. They exhibit multiple responsive DOX release properties (GSH, ROS and temperature) which can adapt to different therapeutic needs. In a tumor microenvironment characterized by elevated levels of GSH and H₂O₂, as well as higher temperatures due to localized hyperthermia, these nanoparticles can switch from a controlled release mode to a rapid release mode. The blank nanoparticles demonstrate excellent biocompatibility. Post-DOX loading, they exhibit low toxicity to normal cells HFF-1 and high in vivo efficacy against HeLa cancer cells. This targeted drug delivery system enhances the water solubility and biocompatibility of a diverse array of toxic hydrophobic drugs, achieving intelligent delivery and multi-modal stimulus-responsive release.