Carbazole-Modified Chiral Ir(III) Complexes for Photodynamic Tumor Therapy: Chirality-Driven Bioactivity and Pyroptosis Activation

Abstract

Phosphorescent metal complexes, as excellent phototheranostic agents, have demonstrated substantial potential in cancer therapy. However, the biological implications of their distinct chirality remain largely unexplored. Herein, we designed and synthesized a pair of carbazole-modified chiral Ir(III) complexes (Δ-Ir-Car and Λ-Ir-Car) as highly potent photosensitizers (PSs) with distinct bioactivities. The incorporation of two carbazole moieties into the Ir(III) complex significantly enhances the singlet oxygen quantum yields for both enantiomers. While displaying nearly identical physicochemical properties in UV–vis absorption, phosphorescence emission, lifetime, and quantum yield, the two enantiomers exhibit remarkable differences in biological performance. Notably, Δ-Ir-Car demonstrates superior cellular uptake, reactive oxygen species (ROS) generation capability, and tumor cell-killing efficiency compared to its Λ-counterpart. Importantly, both complexes induce pyroptosis, a pro-inflammatory cell death pathway, which holds significant potential for overcoming apoptosis resistance and activating antitumor immune responses. This study highlights the critical role of chirality in determining the biological outcomes of metal-based photosensitizers and provides valuable insights for developing chiral metallodrugs with enhanced photodynamic therapeutic efficacy.