2. Academic Validation
  3. Design of photoactivatable methylene blue-bufalin conjugate for GPX4-targeted degradation to induce ferroptosis-like death in breast cancer therapy

Design of photoactivatable methylene blue-bufalin conjugate for GPX4-targeted degradation to induce ferroptosis-like death in breast cancer therapy

  • Bioorg Chem. 2025 Aug:163:108629. doi: 10.1016/j.bioorg.2025.108629.
Xiaoman Mo 1,  Junjie Lan 2,  Yanni Wang 1,  Hang Zhong 1,  Huan He 1,  Zaichang Yang 3,  Silong Zhang 4,  Weidong Pan 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences/Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou University, Guiyang 550025, PR China; Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals/Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, PR China.
  • 2 Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang 550025, PR China.
  • 3 School of Pharmaceutical Sciences/Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou University, Guiyang 550025, PR China; Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals/Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, PR China. Electronic address: yangzaichangzm@163.com.
  • 4 School of Pharmaceutical Sciences/Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou University, Guiyang 550025, PR China; Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals/Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, PR China. Electronic address: silongzhang@whu.edu.cn.
  • 5 School of Pharmaceutical Sciences/Key laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), Guizhou University, Guiyang 550025, PR China; Guizhou Provincial Key Laboratory of Innovation and Manufacturing for Pharmaceuticals/Guizhou Engineering Laboratory for Synthetic Drugs, Guizhou University, Guiyang 550025, PR China. Electronic address: wdpan@163.com.
PMID: 40449152 DOI: 10.1016/j.bioorg.2025.108629
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 4 T1-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.

Keywords

Antitumor; Bufalin; GPX4; Phototherapy; Reactive oxygen species.

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