Amplifying X-ray-Induced Charge Transfer Facilitates Direct Sensitization of Photosensitizers in Radiotherapy

  • ACS Nano. 2025 May 6;19(17):16775-16793. doi: 10.1021/acsnano.5c01506.
Da Zhang  1  2 ,  Qingjing Chen  1  2 ,  Junrong Zhang  3 ,  Xiaohua Xing  1  4 ,  Yang Zhou  1  2 ,  Xiangyu Ou  5 ,  Shuheng Dai  4 ,  Qiushui Chen  4 ,  Xiaolong Liu  1  6  2 ,  Xiaoyuan Chen  7  8  9 ,  Yongyi Zeng  1  10
Affiliations
  • 1. The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, P. R. China.
  • 2. Mengchao Med-X Center, Fuzhou University, Fuzhou 350116, P. R. China.
  • 3. Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, P. R. China.
  • 4. MOE Key Laboratory for Analytical Science of Food Safety and Biology, Fuzhou University, Fuzhou 350108, P. R. China.
  • 5. Department of Physics, Chemistry and Biology (IFM), Linköping University, Linköping SE-58183, Sweden.
  • 6. CAS Key Laboratory of Design and Assembly of Functional Nanostructures, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, P. R. China.
  • 7. Departments of Diagnostic Radiology, Surgery, Chemical and Biomolecular Engineering, and Biomedical Engineering, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore 119074, Singapore.
  • 8. Clinical Imaging Research Centre, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138667, Singapore.
  • 9. Nanomedicine Translational Research Program, NUS Center for Nanomedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 138667, Singapore.
  • 10. Liver Disease Center, The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, P. R. China.
PMID: 40277128 DOI: 10.1021/acsnano.5c01506
Abstract

X-ray-induced photodynamic therapy offers substantial promise for treating deep-seated tumors, but it is still limited by highly inefficient energy transfer processes and the stringent requirements for scintillators with high luminescence quantum yield and significant singlet-triplet intersystem crossing ratios. Herein, we describe X-ray-induced electron-dynamic therapy (X-eDT), which obviates the need for intersystem crossing by exposing nonluminescent hafnium-silica nanoparticles to X-rays, to generate high-energy electrons that can sensitize lower-lying triplet states of various photosensitizers. Our approach strongly induced the production of singlet oxygen (6.18-fold) in vitro even at lower X-ray doses, and in mice it strongly inhibited the growth of xenografts derived from liver, breast, or colon Cancer cell lines (CDX), and growth of patient-derived xenografts (PDX) of hepatocellular carcinoma. In these CDX preclinical systems, X-eDT was not only effective against the irradiated xenograft but also against untreated xenografts in the same animal, and these abscopal effects involved enhanced tumor infiltration by CD4+T cells, CD8+T cells, and IFN-γ-polarized M1 macrophages within the tumor microenvironment. X-eDT even stimulated the production of memory T cells that inhibited rechallenges after treatment. These findings suggest that X-eDT can be effective against primary and metastatic tumors as well as tumor recurrence, which makes it much more powerful than conventional X-PDT.

Keywords
X-ray-induced electron-dynamic therapy; abscopal effect; immunity; metastatic cancer; radiosensitizer; radiotherapy.
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