Radiation-enhanced self-cascade catalytic Ti3C2Tx-based platform enables controlled release of trans-resveratrol for synergistic radiosensitization against metastasis of orthotopic breast cancer

Abstract

Synergistic radiosensitization of cancer cells by metal-based nanomaterials and natural products is a forward-looking alternative for radiotherapy enhancement while inhibiting tumor metastasis. This work explores a phase change material (PCM)-gated Ti3C2Tx nanosheet as a photothermal-responsive drug delivery system for loading natural trans-resveratrol (RSV), aiming at such synergistic radiosensitization in a controlled manner. This system can improve the biodispersity of RSV in the physiological solutions and inhibit the radiation-enhanced enzymatic activity of Ti3C2Tx nanosheets to a large extent. Upon 808 nm near infrared light illimitation, Ti3C2Tx-mediated photothermal heating makes the loaded PCM to be melted, resulting in the controlled release of RSV and simultaneous recovery of radiation-enhanced enzymatic activity of Ti3C2Tx nanosheets. By further irradiating with X-ray, Ti3C2Tx nanosheets is responsible for enhanced catalytic decomposition of H2O2 to highly toxic hydroxyl radical as well as the consumption of intracellular glutathione. Both in vitro and in vivo studies demonstrate that those excess radical oxygen species can synergize with the released RSV to induce cancer cell death by apoptosis/ferroptosis hybrid pathway, fully inhibiting growth and metastasis of orthotopic breast cancer. These results reveal that the combination of PCM-gated Ti3C2Tx nanosheets with RSV is capable of fabricating the photothermal-responsive theranostic systems and aiding the confinement of synergistic radiosensitization exclusively in the cancer cells for radiotherapy enhancement against tumor metastasis.