Controlled Dual Activation of Rhenium(I) Photosensitizers and Profluorophores/Prodrugs via a Dissociative Bioorthogonal Tetrazine-Isonitrile Reaction.

Abstract

Strategies for prodrug activation have been developed to enhance treatment efficacy, with bioorthogonal dissociation reactions emerging as a promising approach due to their remarkable specificity. In this work, we designed three rhenium(I) polypyridine complexes featuring a tetrazylmethyl (TzMe) group capable of bioorthogonal activation by 3-isocyanopropyl (ICPr) or 3-isocyanopropyl-1-carbamoyl (ICPrc) derivatives. This design serves as a dual-release platform, which liberates rhenium(I) 3-hydroxypyridine complexes and functional payloads from rhenium(I) TzMe complexes and ICPr/ICPrc-caged compounds, respectively. Upon incubation with an ICPrc derivative, the TzMe complexes exhibited strong emission in acidic buffers, attributed to the predominant existence of the resulting rhenium(I) 3-hydroxypyridine complexes in their protonated form. Confocal imaging of live cells incubated with a TzMe complex and ICPr-caged fluorescein unveiled intense intracellular emission in distinct channels. Importantly, the therapeutic potential of this approach was underscored by the treatment of cells with a TzMe complex and ICPrc-caged doxorubicin. The anticancer effect was amplified through the synergy between singlet oxygen (1O2) photosensitization and prodrug activation, effectively combining photodynamic therapy with chemotherapy. The more pronounced 1O2 generation of the 3-hydroxypyridine complexes in acidic media and their specific accumulation within the acidic lysosomes of cancer cells highlight the potential of bioorthogonal prodrug activation for effective cancer-targeted therapy.