Tumor Microenvironment-Responsive Cu2(OH)PO4 Nanocrystals for Selective and Controllable Radiosentization via the X-ray-Triggered Fenton-like Reaction

Traditional radiotherapy can induce injury to the normal tissue around the tumor, so the development of novel radiosensitizer with high selectivity and controllability that can lead to more effective and reliable radiotherapy is highly desirable. Herein, a new smart radiosensitizer based on Cu-2(OH)PO4 nanocrystals that can simultaneously respond to endogenous stimulus (H2O2) and exogenous stimulus (X-ray) is reported. First, Cu-2(OH)PO4 nanocrystals can generate Cu-I sites under X-ray irradiation through X-ray-induced photoelectron transfer process. Then, X-ray-triggered Cu-I sites serve as a catalyst for efficiently decomposing overexpressed H2O2 in the tumor microenvironment into highly toxic hydroxyl radical through the Fenton-like reaction, finally inducing apoptosis and necrosis of cancer cells. Meanwhile, this nonspontaneous Fenton-like reaction is greatly limited within normal tissues because of its oxygen-rich condition and insufficient H2O2 relative to tumor tissues. Thus, this strategy can ensure that the process of radiosentization can only be executed within hypoxic tumors but not in normal cells, resulting in the minimum damages to surrounding healthy tissues. As a result, the X-ray triggered Fenton-like reaction via introducing nontoxic Cu-2(OH)PO4 nanocrystals under the dual stimuli provides a more controllable and reliable activation approach to simultaneously enhance the radiotherapeutic efficacy and reduce side effects.