Doubly Stimulated Corrole for Organelle-Selective Antitumor Cytotoxicity

Abstract

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 <b>PC-Im</b>, a theranostic agent with a pH-sensitive <i>N</i>-methylimidazole moiety. Structure/activity relationships, via comparison with the permanently charged <b>PC-ImM</b><b>+</b> and the lipophilic <b>PC</b>, uncovered the exceptional features of <b>PC-Im</b>: 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 <b>PC-Im</b> 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. <b>PC-Im</b> 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.