Organic Carbon Monoxide Prodrugs Activated by Endogenous Reactive Oxygen Species for Targeted Delivery
Inga Černauskienė, Claudio D. Navo, Carlos Labão‐Almeida, Rupert S. J. Proctor, Bengt H. Gless, Wei Ting Khaw, Cong Tang, M. Milagros Muriel-Olaya, Gonzalo Jiménez‐Osés, Gonçalo J. L. Bernardes
Abstract
Carbon monoxide (CO) has demonstrated therapeutic benefits in reactive oxygen species (ROS)-rich environments, such as inflammation and cancer. However, the targeted delivery of CO remains challenging, limiting its clinical application and necessitating the development of improved CO-prodrugs. Herein, we report a radical-activated, metal-free, CO-prodrug designed to address delivery limitations and avoid metal-associated toxicity. This tertiary aldehyde-based prodrug is stable under physiological conditions and, upon activation by a radical trigger, releases CO, 2-ethyl-1-butene, and a nontoxic thiol carrier. The stability of the CO-prodrug building block allows for its incorporation into synthetic peptides via solid-phase peptide synthesis and site-specific bioconjugation to therapeutic antibodies. We synthesized trastuzumab conjugates with a CO-prodrug-to-antibody ratio of 23 and demonstrated efficient, tumor-specific CO release in HER2-high-expressing cells. These findings open new avenues for investigating the therapeutic effects of CO. We anticipate that our metal-free CO-prodrug strategy will be broadly applicable to a wide range of synthetic peptide- and protein-based therapeutics.