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M. Deiana would like to acknowledge financial support from project no. 2022/47/P/NZ5/01156, which is co-funded by the National Science Centre and the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 945339. Funding for J. Jamroskovic was provided by the IMPULZ program of the Slovak Academy of Sciences under the Agreement on the Provision of Funds No. IM-2022-62. L. Lopez-Pacios acknowledges the FPU22/02196 grant from the Spanish Ministry of Science, Innovation and Universities (MICINN). L. Martinez-Fernandez acknowledges the grant PID2023-151719NA-I00 funded by MICIU/AEI/10.13039/501100011033 and FEDER, UE. J. Nogueira thanks the Spanish Ministry of Science and Innovation for funding support through the project CNS2022-135720 (MCIN/AEI/10.13039/501100011033). This research project was made possible through the access granted by the Galician Supercomputing Center (CESGA) to its supercomputing infrastructure. The authors thank Dr Aeson Chang at Monash University (Australia) for carefully reading the manuscript and providing insightful comments. We acknowledge Protein Production Sweden (PPS) for providing facilities and experimental support. PPS is funded by the Swedish Research Council as a national research infrastructure. We thank the members of Dr. Barak's laboratory (Slovak Academy of Sciences) for their help with the initial biochemical experiments. We also thank Dr. Barancik (Slovak Academy of Sciences) for providing access to the Typhoon scanner.

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

Publicated to:NANOSCALE HORIZONS (): - - 2025-06-18 (), DOI: 10.1039/d5nh00237k

Authors: Saczuk, Karolina; Cottini, Maria V; Dudek, Marta; Mazur, Leszek M; Sanchez, Dario Puchan; Lopez-Pacios, Lucia; Kassem, Ahmad; Matczyszyn, Katarzyna; Nogueira, Juan J; Monnereau, Cyrille; Martinez-Fernandez, Lara; Jamroskovic, Jan; Cabanetos, Clement; Deiana, Marco

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Abstract

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(center dot)-) and hydroxyl (OH center dot) 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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