Leucine Aminopeptidase-Activatable Photosensitizer Enables Enzyme-Responsive Photodynamic Therapy in Neuroblastoma

Date

2026-06-03

Author

Karaman, Osman
Kepil, Dilay
Sayin, Asena
Forough, Mehrdad
Ozkan, Erva
Elmazoglu, Zubeyir
Günbaş, Emrullah Görkem

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Photodynamic therapy (PDT) is a minimally invasive and tumor-selective treatment modality; however, despite notable progress in several cancer types, effective treatment options for brain tumors remain limited. Although explored only in a limited number of studies, the intrinsic selectivity of photosensitizers bearing activatable groups makes PDT an attractive strategy for brain cancers. Here, we report, for the first time, the photodynamic efficacy of a leucine aminopeptidase (LAP)-activatable iodinated resorufin derivative (LAP-RI) in neuroblastoma cells (SH-SY5Y). By incorporating a LAP-responsive handle group, the photosensitizer remains silent until enzymatic activation, exploiting the elevated LAP expression in SH-SY5Y observed in this work. This activatable design enabled a measurable, yet modest (similar to 2-fold) enhancement in phototoxicity toward neuroblastoma cells relative to healthy fibroblasts, reflecting enzyme-dependent activation rather than strong intrinsic tumor selectivity. Rather than constituting strong intrinsic cell-line selectivity, this difference reflects enzyme-dependent activation, consistent with elevated LAP activity in SH-SY5Y cells. These findings highlight the potential of resorufin-based, enzyme-activatable photosensitizers as a mechanistically selective platform for PDT of extracranial tumors and underscore the broader promise of activatable PDT agents.

URI

https://hdl.handle.net/11511/119518

Collections

Department of Chemistry, Article