A Novel Nanomedicine for Osteosarcoma Treatment: Triggering Ferroptosis through GSH Depletion and Inhibition for Enhanced Synergistic PDT/PTT Therapy

  1. Tangbing Xu
  2. Qiming Ma
  3. Chi Zhang
  4. Xiaoyan He
  5. Qian Wang
  6. Yunfeng Wu
  7. Kunpeng Qin
  8. Faxue Liao
  9. Ping Zhou
  10. Pengfei Xu
  11. Jialai Yang
  12. Junjun Yang
  13. Jun Chang
  14. Lei Qiao
  15. Yong Hu
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Abstract

Osteosarcoma treatment remains challenging due to the limitations of single-modality therapies.To address this, we designed a carrier-free nanomedicine SRF@CuSO4.5H2O@IR780 (CSIR) for synergistic ferroptosis, photodynamic therapy (PDT), and photothermal therapy (PTT) in osteosarcoma. Interestingly, CSIR could harness the enhanced permeability and retention (EPR) effect to effectively enter tumors. Copper ions (Cu 2+ ) within CSIR could react with the reductive intracellular environment, depleting glutathione (GSH) levels. Near-infrared (NIR) irradiation of CSIR further depleted GSH through reactive oxygen species (ROS) generation. Additionally, CSIR released sorafenib (SRF), which inhibited cystine-glutamate antiporter system xCT (xCT), thereby blocking GSH biosynthesis. RNA sequencing data confirmed ferroptosis induction by CSIR. This synergistic strategy of GSH depletion-induced ferroptosis, enhanced PDT, and photothermal cascade holds promise for improved osteosarcoma treatment and future nanomedicine design.

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  1. Version published to 10.21203/rs.3.rs-5440173/v1 on Research Square