Article Dans Une Revue Nanoscale Horizons Année : 2025

G-quadruplex-driven molecular disassembly and type I-to-type II photophysical conversion of a heavy-atom-free photosensitizer for site-specific oxidative damage

Ahmad Kassem
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Juan J Nogueira
Clément Cabanetos
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Résumé

G-quadruplex (G4)-targeted photosensitizers (PSs) are advancing precision oncology by confining DNA damage to malignant cells while sparing healthy tissue. Yet, molecular-level studies on the mechanisms and dynamics of G4 structure damage under PSs light-activation are limited. Here, we introduce DBI-POE, an activatable, heavy-atom-free PS derived from the G4-specific sulfur-substituted dibenzothioxanthene imide (S-DBI) and modified with a hydrophilic, bio-compatible polyoxyethylene (POE) side chain. In aqueous solution, owing to its amphiphilic character, DBI-POE self-assembles into nanoaggregates that disassemble upon binding to G4 DNA. This disassembly switches its photophysical behavior “turning on” its fluorescence while enabling two-photon near-infrared (NIR) excitation. Moreover, while DBI-POE follows a type I pathway in the aggregated state, producing superoxide anion (O2˙−) and hydroxyl (OH˙) radicals, it shifts to a type II mechanism that predominantly generates singlet oxygen (1O2) upon G4 binding. The generated 1O2 selectively oxidizes guanine residues, triggering G4 unfolding, a mechanism validated through biophysical experiments, dot blot assay and molecular dynamics (MD) simulations. Furthermore, biochemical experiments at single-base resolution reveal that photoactivated DBI-POE induces site-specific oxidative lesions at G4 sites, stalling DNA polymerase, while non-G4 regions remain unaffected. This combination of supramolecular disassembly, photophysical pathway switching, and G4-selective oxidative damage underscores the high specificity of DBI-POE, opening new avenues for the design of next-generation G4-targeted PSs for photodynamic cancer therapies.

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hal-05345250 , version 1 (03-11-2025)

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Karolina Saczuk, Maria V Cottini, Marta Dudek, Leszek M Mazur, Dario Puchán Sánchez, et al.. G-quadruplex-driven molecular disassembly and type I-to-type II photophysical conversion of a heavy-atom-free photosensitizer for site-specific oxidative damage. Nanoscale Horizons, 2025, 10 (8), pp.1660-1673. ⟨10.1039/D5NH00237K⟩. ⟨hal-05345250⟩
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