Intravesical cascade delivery of active monoterpene coumarin for bladder cancer therapy

Abstract

Albumin proteins have been extensively explored for functionalized delivery of therapeutics. However, their potential in intravesical delivery has not been thoroughly investigated. In this work, we developed a green method for the synthesis of albumin nanocarriers that can efficiently encapsulate the active monoterpene coumarin UM-15 and assemble with fluorinated chitosan (FCS) to form UM-15@BSA/FCS nanoparticles (NPs). Upon intravesical perfusion, BSA/FCS NPs serving as the nano-vehicles of UM-15 demonstrate exceptional transepithelial delivery, efficient intratumoral diffusion, and high tumor-targeting uptake capacities. These remarkable advantages can be attributed to their notable cascade delivery performances, which involve FCS-driven rearrangement of bladder epithelium tight junctions and the charge reversal effect-induced dissociation behavior of FCS-albumin complexes, as well as the high tumor selectivity mediated by albumin-binding protein (SPARC) and disulfide bonds. Additionally, UM-15 loaded in those nanovehicles demonstrates significant induction of apoptosis and stemness suppression of bladder cancer cells. With above effects acting synergistically, remarkably improved intravesical treatment outcomes are achieved in both mouse orthotopic and patient-derived orthotopic xenograft models, with reduced toxic side effects. Thus, our study introduces a novel therapeutic agent for BCa therapy and presents a promising avenue for the tumor targeted delivery of therapeutics through an intravesical cascade delivery mechanism.