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Published on: March 7, 2011
Leucine Aminopeptidase-Activatable Photosensitizer Enables Enzyme-Responsive Photodynamic Therapy in Neuroblastoma
Osman Karaman1, Dilay Kepil1, Asena Sayin1
1Department of Chemistry, Middle East Technical University, Çankaya, Ankara 06800, Türkiye.
Abstract:
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 (∼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.
Insights
This study introduces a novel enzyme-activatable photosensitizer for photodynamic therapy (PDT). The leucine aminopeptidase-activated resorufin derivative (LAP-RI) shows potential for treating neuroblastoma by targeting elevated enzyme activity.
Area of Science:
- Biochemistry
- Photochemistry
- Oncology
Background:
- Photodynamic therapy (PDT) offers a minimally invasive, tumor-selective approach.
- Effective PDT options for brain tumors are limited.
- Activatable photosensitizers are promising for brain cancer due to their inherent selectivity.
Purpose of the Study:
- To evaluate the photodynamic efficacy of a leucine aminopeptidase (LAP)-activatable iodinated resorufin derivative (LAP-RI) in neuroblastoma cells.
- To investigate the enzyme-dependent activation of LAP-RI by exploiting elevated LAP expression in SH-SY5Y cells.
Main Methods:
- Synthesis and characterization of the LAP-RI photosensitizer.
- Assessment of phototoxicity in neuroblastoma (SH-SY5Y) and healthy fibroblast cell lines.
- Evaluation of LAP enzyme activity in SH-SY5Y cells.
Main Results:
- LAP-RI demonstrated enzyme-dependent phototoxicity in neuroblastoma cells.
- A modest (approximately 2-fold) enhancement in phototoxicity was observed in neuroblastoma cells compared to fibroblasts.
- The observed selectivity was attributed to elevated LAP activity in SH-SY5Y cells, not intrinsic cell-line selectivity.
Conclusions:
- Resorufin-based, enzyme-activatable photosensitizers show potential for mechanistically selective PDT of extracranial tumors.
- Activatable PDT agents represent a promising strategy for cancer treatment.
- Further research is warranted to explore the broader promise of LAP-activatable PDT agents.
