• A Lysosomal Glycohydrolase-Activatable Photosensitiser for Photodynamic Therapy in Glioblastoma

Glioblastoma (GBM) is one of the most aggressive brain cancers, characterised by high tumour recurrence rates and poor patient outcomes despite administration of common treatment methods. Photodynamic therapy (PDT) has emerged as a promising treatment alternative which utilises a combination of light, oxygen, and photosensitisers (PS) to produce reactive oxygen species (ROS) for targeted cell death. Unfortunately, the clinical efficacy of 5-aminolevulinic (5-ALA), an existing PDT agent, remains variable, inspiring the development of new PSs such as SeNBD-oleic developed by the X group for PDT of GBM. Despite its good phototoxicity and rapid uptake, its lack of specificity for GBM limits its therapeutic potential. To overcome this, an activatable PS with increased uptake in GBM cells was designed, utilising an ‘OFF’ to ‘ON’ mechanism to limit PS activation to target cells. This project therefore reports the synthesis and characterization of activatable A-SeNBD-oleic, a caged derivative of the always ‘ON’ PS, SeNBD-oleic. A-SeNBD-oleic incorporates a cleavable sugar moiety and a carbamate-based self-immolative linker to quench reactive oxygen species (ROS) production in its inactive state. Enzymatic assays indicated selective uncaging of A-SeNBD-oleic in the presence of the lysosomal glycohydrolase, restoring its ROS generation and optical properties. Moreover, in vitro studies with E17 glioma stem cells demonstrated uptake and activation of the PS, leading to significant cytotoxicity under light irradiation. Taken together, these findings illustrate the potential of A-SeNBD-oleic as a phototoxic and selective PS for GBM PDT. Future work will focus on optimizing synthesis yields and evaluating the efficacy and selectivity of A-SeNBD-oleic in ex vivo and in vivo GBM models.