Synthesis of CaCO3-Based Nanomedicine for Enhanced Sonodynamic Therapy via Amplification of Tumor Oxidative Stress

Summary Development of multifunctional stimuli-responsive nanomedicine is appealing for effective cancer treatment. Herein, we utilize the biocompatible CaCO3 nanoparticles as the template to guide the formation of pH-dissociable hollow coordination nanostructures, in which meso-tetra-(4-carboxyphenyl)porphine (TCPP), a sonosensitizer, acts as the organic bridging molecule and ferric ion serves as the metallic center. L-buthionine sulfoximine (BSO), an inhibitor for glutathione (GSH) biosynthesis, can be simultaneously loaded during the preparation of TCPP-Fe@CaCO3, obtaining BSO-TCPP-Fe@CaCO3 with pH-responsive dissociation to endow fast release of Ca2+ and BSO under an acidic tumor microenvironment. Such BSO-TCPP-Fe@CaCO3 confers synergistic oxidative stress amplification via intracellular Ca2+-overloading-induced mitochondria damage, BSO-mediated GSH depletion, and TCPP-mediated sonodynamic therapy (SDT), leading to remarkable cell death. Consequently, tumors on the mice treated with BSO-TCPP-Fe@CaCO3 administration and subsequent ultrasound exposure are effectively suppressed. Our work thus highlights a facile strategy to prepare pH-dissociable nanomedicine for effective SDT treatment of tumors via triple amplification of tumor oxidative stress.