A COMPARATIVE STUDY OF PEROXYNITRITE-RESPONSIVE AND UNCAGED PHENOSELENAZINE PHOTOSENSITIZERS: MECHANISTIC BARRIERS IN ACTIVATABLE PDT

Date

2025-11-27

Author

Harputluoğlu, İrem

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Cancer remains one of the leading causes of mortality worldwide, and the development of effective and selective therapies remains a major clinical challenge. Photodynamic therapy (PDT), based on the light-induced generation of reactive oxygen species, offers a minimally invasive treatment option; however, its clinical utility is limited by poor photosensitizer selectivity and insufficient control over activation within complex tumor microenvironments. Activatable photosensitizers that remain optically inactive until encountering tumor-specific biochemical triggers therefore represent a promising strategy to address these limitations. In this study, two structurally related phenoselenazine-based systems were comparatively evaluated: the photoactive compound NSeOH and its peroxynitrite (ONOO⁻)-responsive caged precursor, NSeOTf. Photophysical analyses demonstrated that NSeOH generates singlet oxygen (¹O?) and Type-I radical species upon excitation at 595 nm, whereas NSeOTf remains photochemically silent until peroxynitrite-mediated decaging occurs. Importantly, this activation process does not directly regenerate NSeOH but instead yields an electronically activated phenoselenazine species, whose resonance-stabilized electronic structure is proposed to be biologically phototoxic. In vitro cytotoxicity studies revealed that, despite its strong photophysical activity, NSeOH induces measurable yet sub-threshold phototoxic effects that do not reach IC50 values under the tested conditions. In contrast, NSeOTf showed no detectable phototoxicity in standard two-dimensional (2D) cell culture models, likely due to insufficient intracellular peroxynitrite levels required for decaging. These findings indicate that photophysical performance alone is insufficient to guarantee PDT efficacy and highlight the critical role of redox-dependent electronic activation within the cellular microenvironment. Overall, this work provides a mechanistic framework illustrating how molecular structure, electronic state modulation, and tumor-associated redox signaling must act synergistically to achieve selective PDT responses. The results offer guiding principles for the rational design of next-generation activatable photosensitizers tailored for oxidative tumor niches.

Subject Keywords

photodynamic therapy, glioblastoma, photosensitizer

URI

https://hdl.handle.net/11511/118311

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Graduate School of Natural and Applied Sciences, Thesis