Doubly Stimulated Corrole for Organelle-Selective Antitumor Cytotoxicity

Balancing
between safety and efficacy of cancer chemotherapeutics
is achievable by relying on internal and/or external stimuli for selective
and on-demand antitumor cytotoxicity. We now introduce the difluorophosphorus­(V)
corrole PC-Im, a theranostic agent with a pH-sensitive N-methylimidazole moiety. Structure/activity relationships,
via comparison with the permanently charged PC-ImM+ and the lipophilic PC, uncovered the exceptional
features of PC-Im: nanoparticular and monomeric at neutral
and low pH, respectively, 10-fold increased light-induced singlet
oxygen production at acidic pH, internalization into malignant cells
within minutes, and selective accumulation within lysosomes. Submillimolar PC-Im concentrations are tolerable in the dark, while illumination
induces nanomolar cytotoxic effects due to a multiplicity of cellular
deleterious events: endoplasmic reticulum fragmentation, lysosome
fusion and exocytosis, calcium leakage, mitochondrial fission, and
swelling. PC-Im emerges as an antitumor agent, whose
potency is triggered by endogenous and exogenous stimuli, assuring
its cytotoxicity will occur selectively upon lysosomal accumulation
and solely upon light activation.