Mechanistic and Kinetic Insights into Rubiadin Phototoxicity: Linking Theory to Photodynamic Efficiency

Phototoxic outcomes in photodynamic therapy depend sensitively on photosensitizer speciation, triplet formation pathways, and oxygen availability. Here, first-principles excited-state dynamics was combined with kinetic modelling to dissect the photochemistry of the plant anthraquinone rubiadin. Ground- and excited-state calculations reveal that the neutral species undergoes barrierless excited state intramolecular proton transfer that channels population into a long-lived triplet reservoir with high ΦT, whereas the monoanion relaxes almost exclusively by internal conversion, quenching phototoxicity. Two-photon cross-sections are intrinsically small, consistent with the asymmetric substitution pattern. Triplet–triplet Dexter transfer to O₂ is exergonic and efficient, while radical-mediated type I/III pathways are hindered by large reorganization energies. These photophysical insights underlie the pH-dependent ΦΔ, with a sharp inflection near the H₂Rbd/HRbd⁻ crossover. Parameterized ordinary differential equation models further quantify how photosensitizer loading, initial oxygen concentration, and oxygen resupply rates control the competition between productive Dexter transfer and nonproductive decay pathways, predicting steep losses in ¹O₂ yield under hypoxic conditions. Collectively, this work highlights the interplay of molecular speciation, triplet dynamics, and oxygen kinetics in governing PDT efficiency and informs strategies for mitigating hypoxia-limited phototoxicity.