High precision tools for intraoperative brain cancer therapy

Abstract

Glioblastoma remains to be the most aggressive brain malignancy to affect adults. The disease has a median survival of only 15 months, owing to tumour recurrence within 2 cm of the primary tumour site. Despite the poor prognosis, standard treatment still relies heavily on surgical resection of the tumours, followed by chemotherapy with temozolomide and radiotherapy. This treatment is hindered by the vast heterogeneity within and between glioblastoma subtypes. In this work, the author has proposed the use of photodynamic therapy as an adjuvant to surgical resection. Photodynamic therapy utilises light to induce a reaction between a photosensitiser and molecular oxygen in order to initiate cell death. This technique centres on three main components; the photosensitiser, light and oxygen. Each of these, in themselves, are non-toxic and cell-death is only elicited when all three are combined. While there are promising candidates for the treatment of glioblastoma through photodynamic therapy, these photosensitisers are often bulky molecules which lack specific targeting groups. This results in side- and off-target effects as well as patient-dependent differences in dosage in the target tissues at the time of treatment. Therefore, a library of photosensitisers based on the nitrobenzoselenadiazole (SeNBD) scaffold was designed. By taking advantage of the low molecular weight of SeNBD, this photosensitiser was readily conjugated to other small molecules, with the overarching aim of targeting glioblastoma metabolism. While differential uptake of metabolites was not effective enough to discriminate between healthy and cancer tissue, a further level of control was added through the design of an activatable photosensitiser. This was achieved by disrupting the electron density within the scaffold, thus quenching the absorbance of the photosensitiser. The nature of these quenching groups can be altered to tune the stimulus which uncages the photosensitiser. As a result, a library of orthogonal and environmentally sensitive photosensitisers based on SeNBD has been created, and this approach applied to other photosensitive scaffolds (i.e. 2-thioxocoumarin, thionaphthalimide, Nile Blue and methylene blue). This highlights the modularity of the approach and the wider implication on developing activatable photodynamic therapy agents. Combining these two strategies paves the way to the development of some of the first enzyme activatable, metabolically targeted photosensitisers. As a model, a cathepsin B sensitive pro-fluorophore was synthesised based on the ONBD scaffold. Transcriptomic data from glioblastoma stem cells (GCGR-E17, GCGR-E31, GCGR-E57) and healthy foetal controls (GCGR-NS12ST_A, GCGR-NS17ST_A, GCGR-NS9FB_B) suggest that this approach can provide an effective route to selective ablation of glioblastoma cells without significant damage to surrounding healthy tissues