Balancing between safety and efficacy of cancerchemotherapeutics is achievable by relying on internal and/orexternal stimuli for selective and on-demand antitumor cytotox-icity. We now introduce the difluorophosphorus(V) corrolePC-Im, a theranostic agent with a pH-sensitiveN-methylimidazolemoiety. Structure/activity relationships, via comparison with thepermanently chargedPC-ImM+and the lipophilicPC, uncoveredthe exceptional features ofPC-Im: nanoparticular and monomericat neutral and low pH, respectively, 10-fold increased light-inducedsinglet oxygen production at acidic pH, internalization intomalignant cells within minutes, and selective accumulation withinlysosomes. SubmillimolarPC-Imconcentrations are tolerable inthe dark, while illumination induces nanomolar cytotoxic effectsdue to a multiplicity of cellular deleterious events: endoplasmic reticulum fragmentation, lysosome fusion and exocytosis, calciumleakage, mitochondrialfission, and swelling.PC-Imemerges as an antitumor agent, whose potency is triggered by endogenous andexogenous stimuli, assuring its cytotoxicity will occur selectively upon lysosomal accumulation and solely upon light activation.
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