Three in One: Viscosity-Sensitive Ruthenium(II) Complexes for Photodynamic Anticancer by Activating Pyroptosis with Self-Evaluation Therapeutic Efficacy and Two-Photon Imaging

The development of a photosensitizer (PS) integrating
real-time
therapeutic monitoring capability represents a critical advancement
in precision photodynamic therapy (PDT). Herein, three ruthenium(II)-triphenylamine
photosensitizers (Ru1–3) were designed and synthesized.
Detailed antitumor mechanism investigations revealed that Ru1 and Ru3 activated caspase-1, induced gasdermin D (GSDMD)
cleavage and mitochondrial membrane potential (MMP) depolarization,
and triggered cell pyroptosis. An increase in the luminescence intensity
of Ru1 and Ru3 was observed during cell
pyroptosis, indicating a significant augmentation of cytoplasmic viscosity
during pyroptosis. Moreover, two-photon excitation experiments verified
that they possessed photocytotoxicity in 3D multicellular tumor spheroids
(MCTSs), and a similar luminescence amplification correlated with
pyroptosis progression was observed. In vivo studies confirmed that Ru3 exhibits superior PDT efficacy and provides real-time
feedback on treatment response via its self-reporting luminescence
characteristics. This work provides new insights into the design and
implementation of multifunctional photosensitizers for tumor cell
pyroptosis with real-time therapeutic monitoring and two-photon imaging.