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

We report a novel cancer-targeting strategy involving the combination of an enzyme-instructed self-assembly (EISA) moiety and a strained cycloalkyne to generate a large accumulation of bioorthogonal sites extracellularly or intracellularly for imaging and therapeutic applications. The generated bioorthogonal sites can serve as activation triggers in different cellular 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 for biological imaging. Additionally, the (photo)cytotoxicity of the large supramolecular assemblies containing the complexes was investigated, and the results illustrate that cellular localization (extracellular or intracellular) imposes a profound impact on the efficiencies of photosensitizers.