Redox‐Inducible Radiomimetic Photosensitizers Selectively Suppress Cancer Cell Proliferation by Damaging DNA through Radical Cation Chemistry.

Fan, Heli; Wang, Luo; Zeng, Xuanwei; Xiong, Chenghe; Yu, Dehao; Zhang, Xiaofan; Chen, Jiayi; Meng, Zhaowei; Campbell, Anahit; Huang, Wanqiao; Mei, Hui; Sun, Huabing

Radiotherapy leverages ionizing radiation to kill cancer cells through direct and indirect effects, and direct effects are considered to play an equal or greater role. Several photosensitizers have been developed to mimic the direct effects of radiotherapy, generating radical cations in DNA models, but none has been applied in cellular studies. Here, we design a radiomimetic photosensitizer, producing DNA radical cations in cells for the first time. To reduce adverse effects, several redox‐inducible precursors are prepared as cancer cells have elevated levels of GSH and H2O2. These precursors respond to GSH or H2O2, releasing the active photosensitizer that captures DNA abasic (AP) sites and generates DNA radical cations upon photolysis, without disrupting the redox state of cells. DNA radical cations migrate freely and are eventually trapped by H2O and O2 to yield DNA lesions, thus triggering DNA damage response. Our study suggests that direct effects of radiotherapy suppress cancer cell proliferation mainly by inducing G2/M phase cell cycle arrest, rather than promoting apoptosis. Synergistic effects of the precursor and chemotherapeutic agents are also observed in combination phototherapy. Beyond highlighting an alternative strategy for phototherapy, this proof‐of‐concept study affords a facile cellular platform to study the direct effects of radiotherapy.

DNA repair; RADICAL cations; CANCER cell proliferation; RADICALS (Chemistry); IONIZING radiation

Angewandte Chemie, 2025, Vol 137, Issue 1, p1

0044-8249

Academic Journal

10.1002/ange.202413352