Microenvironment-controlled and red-light-activatable photocage

Photocages have emerged as powerful tools for enabling precise control over the timing, location and quantity of the released biomolecule of interest. However, most commonly used photocages require activation by UV or violet light, which is cytotoxic. Moreover, the exclusive control of light on their photoreactivity, independent of cell microenvironments, leads to off-target biological effects. In this regard, by exploiting the local polarity-regulated excited state of the solvatochromic probes, we present herein a structurally engineered red-light photocage for microenvironment-dependent activation. This was accomplished through precise modulation of the push-pull framework, resulting in a library of meso-methyl BODIPY-based photocages with varied activation wavelengths. A comprehensive structure-activity relationship investigation of their photophysical parameters and photochemical reactivity demonstrated that photocages with strongly electron-donating substituents exhibited pronounced solvatochromism with their turn-on fluorescence in apolar solvents. On contrary, photocages containing weakly donating groups or lacking donor units did not elicit such a response. We found that solvatochromic photocages bearing fluorinated boron were photochemically silent both in polar and apolar media. However, the photoreactivity was significantly improved by the boron alkylation. The model photocage BPC5 exhibited significantly higher photorelease in apolar media (10% methanol/toluene) than polar media (methanol) upon red-light activation. The results revealed that an apolar environment enables the photoreactivity of BPC5 by promoting the formation of a photochemically active high energy excited state. Moreover, BPC5 displayed clean photoreactivity without compromising its photoconversion quantum efficiency as compared to the photocages of high energy. Collectively, the microenvironment-enabled fluorogenicity and photoreactivity of BPC5 could make it a suitable tool for cell/tissue-specific labeling and subsequent targeted delivery of a cargo to minimize the off-target effect.