No abstract

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)PO 4 nanocrystals that can simultaneously respond to endogenous stimulus (H 2 O 2 ) and exogenous stimulus (X-ray) is reported. First, Cu 2 (OH)PO 4 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 H 2 O 2 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 H 2 O 2 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-raytriggered Fenton-like reaction via introducing nontoxic Cu 2 (OH)PO 4 nanocrystals under the dual stimuli provides a more controllable and reliable activation approach to simultaneously enhance the radiotherapeutic efficacy and reduce side effects.

Radiotherapy (RT) in practical use often suffers from offtarget side effects and ineffectiveness against hypoxic tumor microenvironment (TME) as well as remote metastases. With regard to these problems, herein, we provide semiconductor heterojunction structured WO 2.9 -WSe 2 -PEG nanoparticles to realize a synergistic RT/photothermal therapy (PTT)/checkpoint blockade immunotherapy (CBT) for enhanced antitumor and antimetastatic effect. Based on the heterojunction structured nanoparticle with high Z element, the nanosystem could realize non-oxygen-dependent reactive oxygen species generation by catalyzing highly expressed H 2 O 2 in TME upon X-ray irradiation, which could further induce immunogenic cell death. Meanwhile, this nanosystem could also induce hyperthermia upon near-infrared irradiation to enhance RT outcome. With the addition of anti-PD-L1 antibody-based CBT, our results give potent evidence that local RT/PTT upon mild temperature and low radiation dose could efficiently ablate local tumors and inhibit tumor metastasis as well as prevent tumor rechallenge. Our study provides not only one kind of radiosensitizer based on semiconductor nanoparticles but also a versatile nanoplatform for simultaneous triple-combined therapy (RT/PTT/CBT) for treating both local and metastasis tumors.

Development of an efficient nanoradiosensitization system that enhances the radiation doses in cancer cells to sensitize radiotherapy (RT) while sparing normal tissues is highly desirable. Here, we construct a tumor microenvironment (TME)-responsive disassembled small-on-large molybdenum disulfide/hafnium dioxide (MoS 2 /HfO 2 ) dextran (M/H-D) nanoradiosensitizer. The M/H-D can degrade and release the HfO 2 nanoparticles (NPs) in TME to enhance tumor penetration of the HfO 2 NPs upon near-infrared (NIR) exposure, which can solve the bottleneck of insufficient internalization of the HfO 2 NPs. Simultaneously, the NIR photothermal therapy increased peroxidase-like catalytic efficiency of the M/H-D nanoradiosensitizer in TME, which selectively catalyzed intratumorally overexpressed H 2 O 2 into highly oxidized hydroxyl radicals (•OH). The heat induced by PTT also relieved the intratumoral hypoxia to sensitize RT. Consequently, this TME-responsive precise nanoradiosensitization achieved improved irradiation effectiveness, potent oxygenation in tumor, and efficient suppression to tumor, which can be real-time monitored by computed tomography and photoacoustic imaging.