Exploring a Mitochondria Targeting, Dinuclear Cyclometalated Iridium (III) Complex for Image-Guided Photodynamic Therapy in Triple-Negative Breast Cancer Cells

Abstract

Photodynamic therapy (PDT) has emerged as an efficient and noninvasive treatment approach utilizing laser-triggered photosensitizers for combating cancer. Within this rapidly advancing field, iridium-based photosensitizers with their dual functionality as both imaging probes and PDT agents exhibit a potential for precise and targeted therapeutic interventions. However, most reported classes of Ir(III)-based photosensitizers comprise mononuclear iridium(III), with very few examples of dinuclear systems. Exploring the full potential of iridium-based dinuclear systems for PDT applications remains a challenge. Herein, we report a dinuclear Ir(III) complex (IRDI) along with a structurally similar monomer complex (IRMO) having 2-(2,4-difluorophenyl)pyridine and 4′-methyl-2,2′-bipyridine ligands. The comparative investigation of the mononuclear and dinuclear Ir(III) complexes showed similar absorption profiles, but the dinuclear derivative IRDI exhibited a higher photoluminescence quantum yield (Φp) of 0.70 compared to that of IRMO (Φp = 0.47). Further, IRDI showed a higher singlet oxygen generation quantum yield (Φs) of 0.49 compared to IRMO (Φs = 0.28), signifying the enhanced potential of the dinuclear derivative for image-guided photodynamic therapy. In vitro assessments indicate that IRDI shows efficient cellular uptake and significant photocytotoxicity in the triple-negative breast cancer cell line MDA-MB-231. In addition, the presence of a dual positive charge on the dinuclear system facilitates the inherent mitochondria-targeting ability without the need for a specific targeting group. Subcellular singlet oxygen generation by IRDI was confirmed using Si-DMA, and light-activated cellular apoptosis via ROS-mediated PDT was verified through various live–dead assays performed in the presence and absence of the singlet oxygen scavenger NaN3. Further, the mechanism of cell death was elucidated by an annexin V-FITC/PI flow cytometric assay and by investigating the cytochrome c release from mitochondria using Western blot analysis. Thus, the dinuclear complex designed to enhance spin–orbit coupling with minimal excitonic coupling represents a promising strategy for efficient image-guided PDT using iridium complexes.