Controlled activation is a critical component in prodrug development. Here we report a concentration-sensitive platform approach for bioorthogonal prodrug activation by taking advantage of reaction kinetics. Using two ‘click and release’ systems, we demonstrate enrichment and prodrug activation specifically in mitochondria to demonstrate the principle of the approach. In both cases, the payload (doxorubicin or carbon monoxide) was released inside the mitochondrial matrix following the enrichment-initiated click reaction. Furthermore, mitochondria-targeted delivery yielded substantial augmentation of functional biological and therapeutic effects in vitro and in vivo when compared to controls, which did not result in enrichment. This method is thus a platform for targeted drug delivery that is amenable to conjugation with a variety of molecules and is not limited to cell-surface delivery. Taken together, these two 'click and release' pairs clearly demonstrate the concept of enrichment-triggered drug release and the critical feasibility of treating clinically relevant diseases such as acute liver injury and cancer.
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The authors thank Z. Liu at the Center for Molecular and Translational Medicine at Georgia State University for taking confocal images. The authors also acknowledge GSU Molecular Basis of Disease (Z.P. and M.R.C.), Brains & Behaviors (B.Y.) and University 2CI (L.K.C.d.l.C.) fellowships for their support, and the Department of Defense Peer Reviewed Medical Research Program (W81XWH-16-0464 and NIH R44 DK111260-02 to L.E.O.).
L.E.O. is a scientific consultant for Hillhurst Biopharmaceuticals. All other authors declare no competing interests.
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Zheng, Y., Ji, X., Yu, B. et al. Enrichment-triggered prodrug activation demonstrated through mitochondria-targeted delivery of doxorubicin and carbon monoxide. Nature Chem 10, 787–794 (2018). https://doi.org/10.1038/s41557-018-0055-2
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