Fluorinated Chitosan‐Mediated Transepithelial Delivery of Intravesical Dual‐Drug Immunotherapeutic for Bladder Cancer Therapy

Abstract

Intravesical instillation‐based immunotherapy for bladder‐preservation of bladder cancer (BCa) treatment has not been explored. In the current study, two irrigated nano‐formulations of immunological adjuvant‐fluorinated chitosan (FCS) and therapeutic antibody‐FCS are developed for synergistic immunotherapy against BCa. In this system, FCS is employed as a transepithelial carrier to assemble with bovine serum albumin (BSA)‐flubendazole (FBZ) complex and anti‐PD‐1 (αPD‐1) respectively, to facilitate efficient transepithelial delivery of intravesical FBZ‐BSA and αPD‐1 though transiently regulating the distribution of tight junction proteins on bladder epithelium. In addition, the FBZ–BSA complex exhibits tumor microenvironment‐responsive charge reversal and BSA carrier‐broken effects to drive tumor‐targeted dissociation and drug release of FBZ–BSA/FCS. Moreover, FBZ not only promotes apoptosis and inhibits glycolysis in cancer cells but also displays adjuvant properties to activate potent immune responses through IL‐12/IFN‐γ pathway. Interestingly, combined perfusion of FBZ–BSA/FCS and αPD‐1/FCS nano‐formulations can significantly activate the tumor immune microenvironment, especially CD8+ T cell infiltration and αPD‐1 sensitivity, and finally remarkably inhibit tumor growth in the mouse orthotopic BCa model. Thus, this study presents a novel intravesical delivery platform for ICB antibodies and a smart adjuvant system to achieve potent synergy immunotherapy, which is promising for bladder‐preserving treatment against BCa.