Effects of Biotin on a Fluorescein-Based Photosensitizer Revealed by Multiscale Computational Modeling

Biotinylation of Type II photosensitizers has recently been reported as a new efficient strategy to greatly boost the generation of both superoxide and singlet oxygen. However, the unexpected role of biotin in triggering Type I photoreactions, has not been yet established. We herein provide a thorough multiscale investigation of the effect of biotinylation on a fluorescein-based photosensitizer (1 vs 1-biotin), investigating whether the two-component conjugate is able to contribute to synergistic Type I/Type II photoreactivity. Membrane-interaction studies show that the two agents exhibit a different behavior within the cell membrane despite both spontaneously permeate it even in the absence of biotin receptors. Remarkably, the presence of biotin promotes local accumulation of the dye inside the membrane not observed for the not-functionalized photosensitizer, increasing local bioavailability. Our QM results show that the major effect on the ability to afford Type I-PDT, comes from the different response to the typical acidic tumor microenvironment shown by the biotinylated vs not-substituted compound. To the best of our knowledge, this is the first time that the positive effects of such functionalization have been linked with i) an increased membrane accumulation in absence of specific receptors, ii) a different acid-base equilibrium influenced by its presence.