Fluorinated chitosan mediated transepithelial delivery of sanguinarine-loaded platinum (IV) prodrug for intravesical instillation therapy of muscle-invasive bladder cancer

Cisplatin-based neoadjuvant chemotherapy is first-line strategy to inhibit progression and metastasis of muscle-invasive bladder cancer (MIBC). However, its clinical efficacy is often limited by drug resistance and severe systemic side effects, highlighting the urgent need for innovative therapeutic approaches. Despite advancements in cisplatin-based regimens, research on intravesical cisplatin delivery systems remains scarce. In this study, we developed an amphiphilic platinum(IV) prodrug micellar platform (Pt (IV)-DI-PEG) capable of efficiently encapsulating sanguinarine (San), which was further coated with fluorinated chitosan (FCS) to construct San@Pt(IV)-DI-PEG@FCS nanoparticles (SPFNPs) for intravesical instillation even targeting MIBC. The resulting SPFNPs demonstrated several advantages: the FCS coating facilitated enhanced trans-epithelial drug delivery by regulating bladder epithelial tight junction proteins, enabling efficient intravesical administration; Second, the glutathione (GSH)-responsive reduction of the Pt(IV) prodrug promoted tumor-targeted release of San and localized accumulation of Pt(II), while simultaneously depleting intracellular GSH. Furthermore, the released San induced reactive oxygen species (ROS) production, oxidative cleavage and inhibit the activation and function of poly (ADP-ribose) polymerase, collectively impairing nucleotide-excision repair and preventing the elimination of Pt-DNA adducts, resulting in persistent DNA damage, cell cycle arrest, and apoptosis in tumor cells. The synergistic effects of San and cisplatin were validated in both orthotopic mouse models and patient-derived orthotopic xenograft, demonstrating robust anti-tumor efficacy. This study underscores the potential of intravesical cisplatin formulations as a promising strategy for MIBC treatment, offering a shift from traditional systemic chemotherapy towards localized, targeted drug delivery systems.