Activatable Silicon-Xanthene Photosensitizer for Photodynamic Therapy of Glioblastoma

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KARAMAN O., Kepil D., FOROUGH M., Elmazoglu Z., GÜNBAŞ E. G.

Pharmaceutics, vol.18, no.4, 2026 (SCI-Expanded, Scopus)

  • Publication Type: Article / Article
  • Volume: 18 Issue: 4
  • Publication Date: 2026
  • Doi Number: 10.3390/pharmaceutics18040420
  • Journal Name: Pharmaceutics
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, Directory of Open Access Journals
  • Keywords: activatable PDT agents, glioblastoma, photodynamic therapy, β-galactosidase
  • Open Archive Collection: AVESIS Open Access Collection
  • Middle East Technical University Affiliated: Yes

Abstract

Background: Photodynamic therapy (PDT) offers a promising complementary strategy for treating glioblastoma multiforme (GBM); however, limited control over photosensitizer activation and reduced efficacy under hypoxic conditions remain significant limitations. Methods: In this study, we present the synthesis and functional evaluation of Gal-SiX, an enzymatically activatable Si-xanthene-based activatable PDT agent designed to address these challenges. Prepared via an improved 10-step synthetic route, Gal-SiX exhibits clear turn-on fluorescence and absorbance responses upon β-galactosidase activation and efficiently generates reactive oxygen species in aqueous media. Results: Mechanistic studies revealed that Gal-SiX enables both Type I and Type II PDT pathways, a favorable feature for GBM environments characterized by restricted oxygen availability. In vitro assays conducted on U87MG glioblastoma cells and L929 healthy fibroblasts demonstrated light-dependent cytotoxicity, with IC50 values of 3.30 μM and 7.19 μM, respectively. Gal-SiX also showed minimal dark toxicity (>80 μM) and potent light-induced cytotoxicity, yielding a phototoxicity index of 24.8 in glioblastoma cells. Confocal imaging and MTT assays consistently confirmed enzymatic activation and effective PDT response at the cellular level. Conclusions: Overall, this work introduces the first activatable Si-xanthene-based PDT agent for glioblastoma and provides the first evidence that the Si-xanthene scaffold can support dual Type I/II phototoxicity. These results underscore Gal-SiX’s potential as a PDT platform for addressing the unique constraints of GBM biology.