Bortezomib-Encapsulated Dual Responsive Copolymeric Nanoparticles for Gallbladder Cancer Targeted Therapy

Gallbladder cancer (GBC) is a rare but the most malignant type of biliary tract tumor. It is usually diagnosed at an advanced stage and conventional treatments are unsatisfactory. As a proteasome inhibitor, bortezomib (BTZ) exhibits excellent antitumor ability in GBC. However, the long-term treatment efficacy is limited by its resistance, poor stability, and high toxicity. Herein, BTZ-encapsulated pH-responsive copolymeric nanoparticles with estrone (ES-NP_{(BTZ; Ce6)} ) for GBC-specific targeted therapy is reported. Due to the high estrogen receptor expression in GBC, ES-NP_{(BTZ; Ce6)} can rapidly enter the cells and accumulate near the nucleus via ES-mediated endocytosis. Under acidic tumor microenvironment (TME) and 808 nm laser irradiation, BTZ is released and ROS is generated by Ce6 to destroy the "bounce-back" response pathway proteins, such as DDI2 and p97, which can effectively inhibit proteasomes and increase apoptosis. Compared to the traditional treatment using BTZ monotherapy, ES-NP_{(BTZ; Ce6)} can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES-NP_{(BTZ; Ce6)} demonstrates similar antitumor abilities in patient-derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad-spectrum antitumor formulation.