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

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.

The Coppery Age: Copper (Cu)‐Involved Nanotheranostics

“…[116] In addition to the most explored tumor microenvironmentactivated Fenton reaction for tumor-oxidative therapy by Cu-involved nanocatalysts, the external X-ray as the stimulus was employed for triggering Cu-based Fenton reaction and subsequent tumor-oxidative therapy. [94] In detail, copper hydroxyphosphate nanocatalysts (Cu 2 (OH)PO 4 NC) were initially synthesized followed by further surface mediation with poly(acrylic acid) sodium (PAAS). The exogenous X-ray irradiation converted Cu II sites into Cu I sites, which was more catalytically active in triggering Fenton reaction (Figure 11a).…”

“…In addition, the change of reaction condition (e.g., elevating local temperature) or rational design of synergistic therapy (e.g., PDT/CDT, PTT/CDT, www.advancedsciencenews.com www.advancedscience.com Reproduced with permission. [94] Copyright 2019, American Chemical Society.…”

Strategies based on metal-based nanoparticles for hypoxic-tumor radiotherapy

“…Of these, one of the most applied approaches to reverse the radioresistance of hypoxic tumors is to employ O 2 -elevated nanomaterials to directly harness the O 2 level in solid tumors 19–21. Besides this, some innovative and simple strategies by employing oxygen-independent nanoradiosensitizers have also been explored for hypoxic-tumor RT 22–24. These strategies provide promising opportunities for enhancing the radiotherapeutic efficacy of hypoxic tumors.…”

The Rational Design and Biological Mechanisms of Nanoradiosensitizers

“…The combination of QDs (48 nm) and irradiation induced higher levels of cleaved caspase 3 and apoptosis in H460 cells than did irradiation alone [154]. Cu 2 (OH)PO 4 NPs (5 nm) generated Cu I sites under irradiation, which catalyzed the decomposition of H 2 O 2 into hydroxyl radicals in the tumor microenvironment, resulting in the apoptosis and necrosis of HeLa cells [155]. Cationic nanoscale metal-organic frameworks (nMOFs, <100 nm) containing Hf and Ru elements were targeted to mitochondria, resulting in significant depolarization of the mitochondrial membrane, an increased apoptosis rate, and inhibition of tumor growth in mouse models under irradiation (Figure 4).…”