A Concerted Enzymatic and Bioorthogonal Approach for Extra‐ and Intracellular Activation of Environment‐Sensitive Ruthenium(II)‐Based Imaging Probes and Photosensitizers

• Published in: Angewandte Chemie International Edition Vol. 62; no. 29; pp. e202303931 - n/a
• Main Authors: Shum, Justin, Lee, Lawrence Cho‐Cheung, Chiang, Michael Wai‐Lun, Lam, Yun‐Wah, Lo, Kenneth Kam‐Wing
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 17-07-2023
• Edition: International ed. in English
• Subjects: Assemblies; Bioorthogonal; Controllability; Cytotoxicity; Enzyme-Instructed Self-Assembly; Hydrophobicity; Imaging Agents; Intracellular; Localization; Phosphorescence; Photosensitizers; Probes; Ruthenium; Ruthenium compounds; Self-assembly; Singlet oxygen; Toxicity; Transition metals; Bioorthogonal; Ruthenium; Enzyme-Instructed Self-Assembly; Imaging Agents; Photosensitizers
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202303931

In this article, we report a novel targeting strategy involving the combination of an enzyme‐instructed self‐assembly (EISA) moiety and a strained cycloalkyne to generate large accumulation of bioorthogonal sites in cancer cells. These bioorthogonal sites can serve as activation triggers in different regions for transition metal‐based probes, which are new ruthenium(II) complexes carrying a tetrazine unit for controllable phosphorescence and singlet oxygen generation. Importantly, the environment‐sensitive emission of the complexes can be further enhanced in the hydrophobic regions offered by the large supramolecular assemblies, which is highly advantageous to biological imaging. Additionally, the (photo)cytotoxicity of the large supramolecular assemblies containing the complexes was investigated, and the results illustrate that cellular localization (extracellular and intracellular) imposes a profound impact on the efficiencies of photosensitizers.
A concerted strategy involving enzyme‐instructed self‐assembly to target overexpressed alkaline phosphatases in cancer cells and bioorthogonal reactions for controllable extracellular and intracellular activation of RuII‐based imaging probes and photosensitizers is presented. The emission enhancement, lifetime extension, and (photo)cytotoxicity of the resulting RuII supramolecular assemblies were explored extracellularly and intracellularly.