A Doppler/Near-Infrared-Mediated Visual Real-Time Positioning Microbubble-Based Drug Delivery System Integrating Chemotherapy, Photodynamic Therapy, and Photothermal Therapy for the Treatment of Superficial Tumors

The treatment of superficial tumors is often limited by poor drug targeting and a lack of real-time visualization of drug distribution. To address these challenges, we developed an RGD-modified microbubble system (TF/ICG-MB@RGD) for ultrasound/near-infrared (NIR) dual-modal imaging-guided chemo-photothermal-photodynamic combination therapy. The microbubbles coloaded tegafur (TF), a chemotherapeutic agent, and indocyanine green (ICG), a photothermal and photosensitizing agent, within a lipid shell surrounding a sulfur hexafluoride (SF₆) core. The surface was functionalized with cyclic RGD peptides to achieve active targeting to tumor vasculature. Upon intravenous administration, the system allowed real-time visualization of accumulation in tumor tissue via Doppler ultrasound and NIR imaging. Based on the imaging feedback, an 808 nm laser was applied to trigger rapid release of TF and ICG, simultaneously inducing chemotherapy, hyperthermia, and reactive oxygen species generation. In a 4T1 murine breast cancer model, this strategy resulted in a tumor inhibition rate of 72.76% with minimal systemic toxicity. This integrated approach provides a promising theranostic platform for precision treatment of superficial tumors.