19F MRI/CEUS Dual Imaging-Guided Sonodynamic Therapy Enhances Immune Checkpoint Blockade in Triple-Negative Breast Cancer.

Abstract

Treatment of highly aggressive triple-negative breast cancer (TNBC) in the clinic is challenging. Here, a liposome nanodrug (LP@PFH@HMME) integrating imaging agents and therapeutic agents for bimodal imaging-guided sonodynamic therapy (SDT) is developed, which boosted immunogenicity to enable potent immunotherapy via immune checkpoint blockade (ICB) in TNBC. In the acidic tumor microenvironment (TME), LP@PFH@HMME undergoes "nano-to-micro" transformation due to a pH-responsive lipid fusion, which makes droplets much more sensitive to ultrasound (US) in contrast-enhanced ultrasound (CEUS) and SDT studies. The nanodrug demonstrates robust bimodal imaging ability through fluorine-19 magnetic resonance imaging (¹⁹F MRI) and CEUS bimodal imaging, and it exhibits excellent solubility in aqueous solution with relatively high ¹⁹F content and desirable long transverse relaxation time (T₂ = 1.072 s), making it suitable for high-performance ¹⁹F MRI, in addition to effective accumulation of nanodrugs after tail vein injection. Thus, ¹⁹F MRI/CEUS dual imaging is achievable to show adequate time points for US irradiation of tumor sites to induce highly effective SDT, which produces abundant reactive oxygen species (ROS) triggering immunogenic cell death (ICD) to assist ICB-based immunotherapy. The combination treatment design of sonodynamic therapy with immunotherapy effectively inhibited TNBC growth and recurrence, highlighting the promise of multifunctional nanodrugs in treating TNBC.