Enhancing Photodynamic Therapy Efficacy Against Cancer Metastasis by Ultrasound-Mediated Oxygen Microbubble Destruction to Boost Tumor-Targeted Delivery of Oxygen and Renal-Clearable Photosensitizer Micelles

Hypoxic tumor microenvironment and nonspecific accumulation of photosensitizers are two key factors that limit the efficacy of photodynamic therapy (PDT). Herein, a strategy of oxygen microbubbles (MBs) boosting photosensitizer micelles is developed to enhance PDT efficacy and inhibit tumor metastasis by self-assembling renal-clearable ultrasmall poly(ethylene glycol)-modified protoporphyrin IX micelles (PPM) and perfluoropentane (PFP)-doped oxygen microbubbles (OPMBs), followed by ultrasound imaging-guided OPMB destruction to realize the tumor-targeted delivery of PPM and oxygen in tumor. Doping PFP into oxygen MBs increases the production of MBs and stability of oxygen MBs, allowing for persistent circulation in blood. Following co-injection, destruction of OPMBs with ultrasound leads to ∼2.2-fold increase of tumor-specific PPM accumulation. Furthermore, the burst release of oxygen by MB destruction improves tumor oxygenation from 22 to 50%, which not only raises the production of singlet oxygen but also significantly reduces the expression of hypoxia-inducible factor-1 alpha and related genes, thus preventing angiogenesis and epithelial-mesenchymal transition. It is verified that this strategy effectively eradicates orthotopic breast cancer and inhibits lung metastasis. Furthermore, the survival rate of mice bearing orthotopic pancreatic tumor is significantly extended by such interventional PDT strategy. Therefore, the combination of ultrasmall PPM and OPMBs represents a simple but effective strategy in overcoming the limitations of PDT.