Modified peroxamide-based reactive oxygen species (ROS)-responsive doxorubicin prodrugs.
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Description
Reactive oxygen species (ROS) plays a pivotal physiological role in intracellular signaling of any living organism. Due to the elevated levels of ROS in tumor microenvironment than normal tissues, an increasing number of ROS-responsive probes and prodrugs is being studied for the fight against cancer. This study describes the design and synthesis of a panel of novel modified peroxamide-based ROS-responsive prodrugs of doxorubicin, among which the OH-mOX-Dox prodrug showed very stable and highly specific ROS sensitivity. This novel Dox prodrug exerted potent anti-proliferation effects against the two breast cancer cell lines of MDA-MB-468 and MDA-MB-231 while it showed minimal toxicity toward the normal breast cell line, MCF-12A. The cytotoxicity of the OH-mOX-Dox prodrug was significantly enhanced at elevated ROS levels after co-incubation with l-buthionine sulfoximine (BSO). Our clonogenic assay data validated that enhanced intracellular ROS level upon X-ray irradiation resulted in an increase in the efficacy of the OH-mOX-Dox prodrug against the two breast cancer cell lines.
Affiliations
- Chemical Engineering Program, Department of Chemical and Environmental Engineering, University of Cincinnati, Cincinnati, OH 45221, United States.
- Chemical Engineering Program, Department of Chemical and Environmental Engineering, University of Cincinnati, Cincinnati, OH 45221, United States. Electronic address: joo.lee@uc.edu.
- Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, United States.
- Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221, United States; Department of Biomedical Education, California Health Science University, Clovis, CA 93611, United States.