Phenazine Cations as Anticancer Theranostics^†

Area of Science:

• Medicinal Chemistry
• Photochemistry
• Cell Biology

Background:

• Polypyridyl compounds are versatile ligands for photoactive metal complexes.
• Investigating their biological properties is crucial for therapeutic applications.
• Understanding structure-activity relationships guides the design of novel agents.

Purpose of the Study:

• To investigate the biological properties and therapeutic potential of two water-soluble polypyridyl organic cations.
• To evaluate their cytotoxicity, cellular uptake, and mechanism of action.
• To assess their preliminary toxicity in an animal model.

Main Methods:

• Cytotoxicity screening across various cell lines.
• Cellular uptake studies using intrinsic luminescence.
• Confocal microscopy and stimulated emission depletion (STED) nanoscopy.
• Transmission electron microscopy (TEM) for ultrastructural analysis.
• Galleria melonella toxicity assay.

Main Results:

• Both cations exhibited selective cytotoxicity against cancer cells versus HEK293 cells.
• The more extended cation showed enhanced photoactivity, inducing cell death at nanomolar concentrations upon visible light irradiation.
• Cellular uptake studies revealed preferential internalization of the more lipophilic cation.
• Treatment led to lysosomal swelling, mitochondrial dysfunction, and lysosome-dependent cell death (necrosis and apoptosis).
• No detectable toxicity was observed in the Galleria melonella model up to 80 mg/kg.

Conclusions:

• Polypyridyl organic cations represent a promising class of photoactive compounds for therapeutic development.
• The active cation demonstrates potent, light-activated cytotoxicity with a favorable preliminary safety profile.
• Further investigation is warranted to explore their therapeutic efficacy and optimize their design.