The biological properties
of two water-soluble organic
cations
based on polypyridyl structures commonly used as ligands for photoactive
transition metal complexes designed to interact with biomolecules
are investigated. A cytotoxicity screen employing a small panel of
cell lines reveals that both cations show cytotoxicity toward cancer
cells but show reduced cytotoxicity to noncancerous HEK293 cells with
the more extended system being notably more active. Although it is
not a singlet oxygen sensitizer, the more active cation also displayed
enhanced potency on irradiation with visible light, making it active
at nanomolar concentrations. Using the intrinsic luminescence of the
cations, their cellular uptake was investigated in more detail, revealing
that the active compound is more readily internalized than its less
lipophilic analogue. Colocalization studies with established cell
probes reveal that the active cation predominantly localizes within
lysosomes and that irradiation leads to the disruption of mitochondrial
structure and function. Stimulated emission depletion (STED) nanoscopy
and transmission electron microscopy (TEM) imaging reveal that treatment
results in distinct lysosomal swelling and extensive cellular vacuolization.
Further imaging-based studies confirm that treatment with the active
cation induces lysosomal membrane permeabilization, which triggers
lysosome-dependent cell-death due to both necrosis and caspase-dependent
apoptosis. A preliminary toxicity screen in the Galleria
melonella animal model was carried out on both cations
and revealed no detectable toxicity up to concentrations of 80 mg/kg.
Taken together, these studies indicate that this class of synthetically
easy-to-access photoactive compounds offers potential as novel therapeutic
leads.