PROJECT SUMMARY Phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is an alternative cancer treatment modality based on the ability of photosensitizers (PSs) to convert photon energy into reactive oxygen species (ROS， i.e. singlet oxygen, superoxide anion, hydroxyl free radical, etc.) or heat. PDT/PTT treatment has special selectivity because the treatment only becomes effective when the PS is activated by light. PDT/PTT has the advantages of noninvasiveness, little or no scarring due to the fast healing process, and being able to treat the patients in an outpatient setting. However, the drawbacks of currently available porphyrin-based PSs, such as the inability to be activated by near-IR (NIR) light, low ROS generation efficiency in hypoxic solid tumors, low selectivity for cancerous tissue, and long-lasting cutaneous photosensitivity, have limited the application of PDT to superficial tumors. To solve these problems, we plan to apply our newly developed strong NIR-absorbing PS BODIPY-Ir to PDT/PTT by encapsulating it into cancer specific targeting, H2O2-activatable, and O2-evolving micelles to efficiently produce ROS in hypoxia. We hypothesize that the proposed micelles loaded with the NIR-absorbing Ir(III) PS can specifically target tumors and be activated by H2O2 and efficiently generate more toxic forms of ROS than H2O2 to improve the PDT efficiency under hypoxia. Three Specific Aims will be pursued in this project - Aim 1: To encapsulate our NIR PS BODIPY-Ir into H2O2-activatable and O2-evolving micelles for cancer-specific targeting and efficient ROS generation in hypoxia; and to evaluate the micelle encapsulation, release, ROS generation in hypoxia, and photothermal conversion efficiency in PBS solutions; Aim 2: To evaluate the in vitro inhibition of growth, migration and invasion of breast cancer cells by new-generation BODIPY-Ir micelle PDT/PTT; Aim 3: To evaluate the in vivo therapeutic outcomes of inhibiting tumor growth and metastasis following new-generation BODIPY-Ir micelle PDT/PTT treatment. Breast cancer cell lines, MDA MB-231 and 4T1, and tumor model Balb/c mice/4T1 will be used to test our hypothesis in vitro and in vivo, respectively. Our long-term objective is to advance the PDT/PTT modality for a more effective and much safer cancer therapy of triple-negative breast cancer. Twelve undergraduate students including Native American students will be trained in this project. The participating students will be involved in all scientific aspects of this project, including PS synthesis, micelle formation and characterization, photophysical studies, and in vitro and in vivo photobiological studies, from which they will be extensively trained on various biomaterials and biomedical research lab skills. These students will also be trained on literature usage, data collection and analysis, scientific writing and presentation, time management, and communication / interpersonal skills. More importantly, ou...