Heavy Atom‐Free, Mitochondria‐Targeted, and Activatable Photosensitizers for Photodynamic Therapy with Real‐Time In‐Situ Therapeutic Monitoring

Based on spin‐orbit charge transfer intersystem crossing mechanism, two heavy‐atom‐free photosensitizers (PSs) BDP1/BDP2 with absorption maxima at 506 nm/660 nm were constructed for photodynamic therapy (PDT). The long triplet state lifetimes and large singlet oxygen quantum yields, coupled with the mitochondria‐targeted feature, made them highly phototoxic toward cancer cells. Moreover, the PDT‐promoted cell apoptosis could be monitored by an obvious fluorescence off‐on response of the two PSs due to the concomitant activation of extensive mitophagy, thus facilitating timely therapeutic feedback to avoid under‐ or over‐treatment. Importantly, such design allows the activatable PSs Glu‐BDP1/Glu‐BDP2 to be fabricated by attaching γ‐glutamyl, a substrate of γ‐glutamyltranspeptidase, to the alkoxyaniline unit of BDP1/BDP2, and their ability in either selectively killing cancer cells over normal cells or in ablating implanted tumour without damage to healthy tissue was demonstrated. A new class of heavy‐atom‐free and mitochondria‐targeted photosensitizers (PSs) with the real‐time in situ self‐reporting ability was constructed for photodynamic cancer therapy. Based on the platform, activatable PSs were further developed, and their ability in either selective killing of cancer cells over normal cells or in effectively ablating an implanted tumour without damage to healthy tissue was demonstrated.