ROS‐Activatable Prodrug of Doxazolidine as Novel Cancer Therapy Paradigm

Overcoming severe side effects from anticancer agents without decreasing their effects on tumor growth is a major challenge. A prodrug technology is reported using agents that are spatiotemporally activated primarily in tumors while the extratumoral toxicity to healthy cells is minimized. A ROS‐acti...

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Bibliographic Details
Published in:Advanced therapeutics 2024-12, Vol.7 (12), p.n/a
Main Authors: Tamura, Ryo, Carpenter, Chace I., Thomas, Charlotte M., Kamyabi, Ghazal, Hsu, Hsiao‐Ting, Vergnolle, Olivia, Balderes, Paul, Grimm, Jan
Format: Article
Language:English
Subjects:
cancer
chemotherapy
drug resistance
radiology
radionuclides
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Summary:Overcoming severe side effects from anticancer agents without decreasing their effects on tumor growth is a major challenge. A prodrug technology is reported using agents that are spatiotemporally activated primarily in tumors while the extratumoral toxicity to healthy cells is minimized. A ROS‐activatable prodrug of a strong anticancer agent, doxazolidine (doxaz), is developed. Doxaz is a DNA alkylating agent with a half‐life of 3 min and significantly higher cytotoxicity than the clinically used parental compound doxorubicin (dox). Importantly, doxaz is not affected by p‐glycoprotein expression since it irreversibly alkylates DNA while dox inhibits the topoisomerase II DNA complex. As drug activators, reactive oxygen species (ROS) are already produced inside cancer cells in higher abundance than in normal cells but additionally generated by external stimuli such as radionuclides (via radiolysis of water) and/or ROS‐inducing drugs. We synthesized the prodrug, Doxaz‐BA, and evaluated its efficacy in vitro in cell cultures and then in vivo in xenograft mouse models. Doxaz‐BA is effective in a broad range of cancer cells since most cancer cells produce higher levels of ROS. Combining with clinically relevant radiotracers such as 18F‐FDG or other tumor‐tropic agents / ROS inducing drugs results in a tumor‐specific and enhanced localized therapy paradigm. The development of a treatment paradigm for drug‐resistant metastatic tumors using a prodrug that is activated by the abnormal metabolism of cancer cells and external stimuli such as the tumor‐tropic agent 18F‐FDG.
ISSN:2366-3987
2366-3987
DOI:10.1002/adtp.202400340