Glutathione‐Sensitive Photosensitizer–Drug Conjugates Target the Mitochondria to Overcome Multi‐Drug Resistance in Cancer

• Published in: Advanced science 2024-08, Vol.11 (30), p.e2307765-n/a
• Main Authors: Song, Weiguo, Yang, Hekai, Wang, Ying, Chen, Shuzhen, Zhong, Wenda, Wang, Qian, Ding, Wenshuo, Xu, Guangzhao, Meng, Chen, Liang, Ying, Chen, Zhe‐Sheng, Cao, Shuhua, Wei, Liuya, Li, Fahui
• Format: Article
• Language: English
• Subjects: cancer multi‐drug resistance; Cancer therapies; Chemical bonds; Chemotherapy; Drug delivery systems; Drug resistance; GSH sensitive; Light; Mitochondria; mitochondria ‐ targeting; NMR; Nuclear magnetic resonance; photodynamic therapy; Side effects; the combination of photodynamic therapy and chemotherapy; Toxicity
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202307765

Multi‐drug resistance (MDR) is a major cause of cancer therapy failure. Photodynamic therapy (PDT) is a promising modality that can circumvent MDR and synergize with chemotherapies, based on the generation of reactive oxygen species (ROS) by photosensitizers. However, overproduction of glutathione (GSH) by cancer cells scavenges ROS and restricts the efficacy of PDT. Additionally, side effects on normal tissues are unavoidable after PDT treatment. Here, to develop organic systems that deliver effective anticancer PDT and chemotherapy simultaneously with very little side effects, three GSH‐sensitive photosensitizer‐drug conjugates (CyR‐SS‐L) are designed and synthesized. CyR‐SS‐L localized in the mitochondria then is cleaved into CyR‐SG and SG‐L parts by reacting with and consuming high levels of intracellular GSH. Notably, CyR‐SG generates high levels of ROS in tumor cells instead of normal cells and be exploited for PDT and the SG‐L part is used for chemotherapy. CyR‐SS‐L inhibits better MDR cancer tumor inhibitory activity than indocyanine green, a photosensitizer (PS) used for PDT in clinical applications. The results appear to be the first to show that CyR‐SS‐L may be used as an alternative PDT agent to be more effective against MDR cancers without obvious damaging normal cells by the combination of PDT, GSH depletion, and chemotherapy. A glutathione‐sensitive photosensitizer‐drug is firsted designed to simultaneously realize tumor photodynamic therapy and chemotherapy. The disulfide linkage in predrug is broken by glutathione reductase, releasing active photosensitizers and Lonidamine. Due to the synergistic effect, the expression of ATP‐binding cassette subfamily B member 1 (ABCB1) is reduced and the drug resistance pathway is broken, resulting to the efficient cancer treatment.