Convergence of Photophysical and Biological ROS Generation to treat disseminated tumors

Applications of photodynamic therapy (PDT) in treating diverse human diseases have improved outcomes through a variety of cell death pathways that include the generation of reactive oxygen species (ROS) and the stimulation of immune system. A significant limitation of PDT is the shallow penetration of light in tissue, preventing its efficient use to treat disseminated tumors. To address this challenge, we developed radionuclide stimulated dynamic therapy (RaST), where radioactive materials capable of emitting Cerenkov radiation stimulates photosensitizers to generate cytotoxic ROS for cancer treatment. Using multiple myeloma cells in mice, we found that RaST achieved durable progression-free survival in mice, but the disease eventually relapsed. In contrast, combination of RaST with a proteasome inhibitor and ROS generator, bortezomib, exerted sustainable disease-free survival, with 60% complete response in a disease governed by frequent relapse. Given that bortezomib was used at a non-pharmacological dose, our study demonstrates that combining biological with photophysical intracellular ROS production efficiently depletes the heterogeneous population of cancer cells to inhibit cancer relapse.