Sequential Design of Activatable Photosensitizers for Ablation of Glioma Cells in Brain Cancer Tissues
Utsa Karmakar, Zhiming Cheng, Andrew D. M. Green, Sam Benson, Eleni Nestoros, Clarissa Lim, Justyna Cholewa‐Waclaw, Fabio de Moliner, Paula Lusarreta, Deborah Seah, Alsadeg Bilal, Neza Alfazema, Thibaud Aymoz‐Bressot, Gillian Morrison, Sonja Vermeren, Steven M. Pollard, Paul M. Brennan, Michael G. Tanner, Marc VendrellABSTRACT
Photodynamic therapy (PDT) is a promising strategy to eradicate residual glioma cells in brain cancer patients; however, current photosensitizers (PS) show limitations on selective accumulation and controlled activation in glioma cells. In this work, we present the design, synthesis, and characterization of activatable PSs for selective PDT of glioma cells in mouse and human brain tissues. First, we designed and characterized a broad collection of photosensitive metabolite conjugates, from which we prepared Gal‐SeNBD‐oleamide as a β‐galactosidase‐responsive PS with efficient uptake in patient‐derived glioma cells and selectivity over immune cells. Furthermore, we optimized a whole‐tissue illumination strategy using Gal‐SeNBD‐oleamide in mouse brain slices, which led to efficient ablation of cancer cells with minimal damage to surrounding regions. Finally, the proof‐of‐concept application of Gal‐SeNBD‐oleamide directly in tissues from brain cancer patients supports its translational potential for PDT of glioblastoma.