A Bivalent Iridium(III) Complex Toolkit for Mitochondrial DNA G-Quadruplex-Targeted Theranostics.

Area of Science:

• Medicinal Chemistry
• Biochemistry
• Oncology

Background:

• G-quadruplexes (G4s) are crucial targets in cancer diagnostics and therapeutics.
• Developing theranostic probes for subcellular G4s presents significant challenges.
• Triple-negative breast cancer (TNBC) requires innovative diagnostic and therapeutic strategies.

Purpose of the Study:

• To design and synthesize novel G4-targeted theranostic probes.
• To evaluate the probes' efficacy in detecting and treating TNBC cells.
• To explore the potential of these probes for subcellular G4 visualization and therapy.

Main Methods:

• Conjugation of a pyridostatin-derived G4 ligand to G4-specific iridium(III) complexes.
• Assessment of probes' luminescence properties in TNBC cells, focusing on mitochondrial G4.
• Evaluation of photodynamic therapy (PDT) efficacy, including reactive oxygen species (ROS) generation and apoptosis induction.

Main Results:

• Probes exhibited specifically enhanced luminescence towards mitochondrial G4 in TNBC cells.
• Complex 3 demonstrated near-infrared (NIR) emission and selectivity for TNBC cells over normal cells.
• Probes induced significant PDT toxicity in TNBC cells via ROS-mediated apoptosis; Complex 3 showed a hybrid PDT effect potentially overcoming hypoxia.

Conclusions:

• The developed iridium(III) complexes serve as multicolor and modular phototheranostic probes for DNA G4s.
• Complex 3 shows promise as a theranostic agent for TNBC, with potential for selective imaging and hypoxia-resistant therapy.
• This work provides a versatile theranostic toolkit for investigating subcellular DNA G-quadruplex functions in cancer.