Photoclick and Release for Spatiotemporally Localized Theranostics of Single Cells via In Situ Generation of 1,3-Diaryl-1H-benzo[f]indazole-4,9-dione.

Abstract

Bioorthogonal click-release chemistry is a cutting-edge tool for exploring and manipulating biomolecule functions in native biological systems. However, it is challenging to achieve the precise regulation or therapy of individual cells via click-release strategies driven by proximity and thermodynamics. Herein, we propose a novel photoclick-release approach based on a photo-induced cycloaddition between 4,4'-bis(N-arylsydnone) or C-bithienyl-diarylsydnone and 2-arylamino-naphthoquinone via irradiation with 405 or 485 nm light. It constructs 1,3-diaryl-1H-benzo[f]indazole-4,9-dione (BIZON) as a pharmacophore while releases an arylamine for fluorescence turn-on probing. Both photoclick reagents were tailored by connecting to the triphenyl phosphonium delivery motif for enrichment in the mitochondria of live cells. This enables an intracellular photoclick and release under the control of 405 or 485 nm light. We then discovered that the in situ photo-generated BIZON is capable of photosensitizing upon 485 or 520 nm light to produce singlet oxygen inside the mitochondria under aerobic conditions. Therefore, we realized wash-free fluorescence tracking and subsequent anti-cancer efficacy at single-cell resolution using global illumination, which provides a foundation for wavelength-gated single-cell theranostics.