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Glutathione-Sensitive Photosensitizer-Drug Conjugates Target the Mitochondria to Overcome Multi-Drug Resistance in Cancer.

ABSTRACT: 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.

SUBMITTER: Song W

PROVIDER: S-EPMC11321625 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Glutathione-Sensitive Photosensitizer-Drug Conjugates Target the Mitochondria to Overcome Multi-Drug Resistance in Cancer.

Song Weiguo W Yang Hekai H Wang Ying Y Chen Shuzhen S Zhong Wenda W Wang Qian Q Ding Wenshuo W Xu Guangzhao G Meng Chen C Liang Ying Y Chen Zhe-Sheng ZS Cao Shuhua S Wei Liuya L Li Fahui F

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20240619 30

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 ef ...[more]

PMID: 38898730

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Dataset Information

Glutathione-Sensitive Photosensitizer-Drug Conjugates Target the Mitochondria to Overcome Multi-Drug Resistance in Cancer.

Publications

Glutathione-Sensitive Photosensitizer-Drug Conjugates Target the Mitochondria to Overcome Multi-Drug Resistance in Cancer.

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