Gold nanoparticle doped Cuhemin nanosheets with a remodeling tumor microenvironment for multiple radiotherapy sensitization

Abstract

Effective radiosensitizers are urgently needed due to the serious negative effects that high radiation doses might have. We created an integrated nano-system (Cuhemin–Au) made of Cuhemin nanosheets and Au nanoparticles (Au NPs) for sensitizing radiotherapy to solve this issue. This system can manifest enzyme-like activities to universally suppress the resistance pathways in breast cancer cells for amplifying radiation damage. Cuhemin–Au NPs increase the energy deposition of radiation owing to the high X-ray attenuation coefficient of Au. In addition, Cuhemin–Au has peroxidase (POD)-like and glucose oxidase (Gox)-like activity, and can also consume intracellular GSH, which can reduce intracellular GSH levels to reduce tumor cells' capacity to repair DNA and deplete intracellular glucose via their characteristic Gox-like catalytic activities, which can cause an increase in the oxidative stress and further produce H₂O₂. Cuhemin–Au then produced ˙OH, which upsets redox equilibrium and destroys mitochondria, leading to radiation sensitivity, after reacting with enough hydrogen peroxide in tumor cells. Cuhemin–Au combined with low dose RT (4 Gy) could significantly limit tumor development with fewer adverse effects, according to in vivo and in vitro experiments. This platform generated a fresh concept for the construction of a radiotherapy sensitization system and accomplished synergistic radiotherapy sensitization.