Design of Photoactivatable Methylene Blue-Bufalin Conjugate for Gpx4-Targeted Degradation to Induce Ferroptosis-Like Death in Breast Cancer Therapy

Abstract

Bufalin is a potent antitumor agent; however, its high toxicity limits its clinical application. Here, we explored the development of a novel photosensitizer-small molecule conjugate, MB-Buf, which combines the photosensitizer methylene blue (MB) with bufalin. The goal is to achieve targeted photodegradation of GPX4 upon light activation. The compound MB-Buf integrates the photodynamic properties of MB with the antitumor activity of bufalin. Under light irradiation, it generates reactive oxygen species (ROS), exhibiting photodynamic therapeutic activity, while its toxicity toward normal cells is reduced by 15-fold compared to bufalin alone. In vivo studies using a 4T1-Luci xenograft mouse model demonstrated that MB-Buf, in combination with light irradiation, significantly inhibits tumor growth. These findings support MB-Buf as a promising new cancer treatment strategy, offering a potential approach to overcome the limitations of conventional therapies.

Note:
Funding declaration: This work was supported by the National Natural Science Foundation of China (82273818, 82473815), the Guizhou Provincial Basic Research Program (Natural Science) (No. qianhejichu-MS [2025] 688), the Natural Science Foundation (Special Position) of Guizhou University (GDTGHZ [2022]59), the Guizhou Provincial People's Hospital Talent Fund Project (YRCXM [2022]-24), the Guizhou Provincial Basic Research Program (Natural Science) (No. QKHJC〔2024〕Youth 292).

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval: All animal experiments were conducted in accordance with the Guidelines for Laboratory Animal Research of Guizhou University (No. EAE-GZU 2022-E045) and approved in principle by the Committee for the Protection and Use of Laboratory Animals of Guizhou University.

Keywords: bufalin, GPX4, phototherapy, reactive oxygen species, antitumor