Metabolic photosensitizers for photodynamic therapy of brain cancer.

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Glioblastoma is the most aggressive primary brain tumour and the cancer with the most years of potential life lost in adults. Even with optimal surgery, the median survival is only around 15 months. This is mainly due to the infiltrative nature of glioblastoma and to the presence of cancerous cells close to untouchable structures, which hinders complete removal of the tumour mass. This unmet clinical need drives the development of a new technology to aid surgeons optimise tumour resection and ablation without damaging healthy tissue.Our technology builds on photodynamic therapy (PDT), a clinical approach that ablates cells via oxidative stress caused by light-activatable photosensitisers (PS). PDT is currently not available for routine treatment of glioblastoma, but it could be used to target residual tumour cells close to vital structures as more than 98% of brain tumours recur within few mm of the resection margin. Current PDT agents (e.g., 5-aminolevulinic acid or 5-ALA) have major limitations as a PDT agent for ablation of glioblastoma: 1) 5-ALA takes several hours (between 2 and 5 h) to be 'active' and this time varies between patients, making the dosing difficult to optimise for each patient; 2) 5-ALA has limited sensitivity and selectivity, which results in off-target localisation and failure to achieve maximal safe tumour resection.To improve the existing PDT approaches for the treatment of glioblastoma, we aim to:1 - Develop new PS that can selectively enter brain cancer cells within minutes after topical administration during surgical interventions. The safety and efficacy of these new agents will be examined in human cells and tissues from patients.2- Design cost-effective devices for the safe delivery of non-toxic light of appropriate wavelengths, power and surface area coverage for brain surgery. These standardised systems will increase the usability of PDT in surgical interventions, making it a more practical and widely used approach for the treatment of glioblastoma.Altogether, this new approach will allow clinicians to optimise tumour ablation in a patient-specific manner, maximising sensitivity and specificity while minimising the side effects derived from systemic administration and off-target accumulation.This proposal builds upon the SeNBD technology pioneered by the PI's team (patent application: WO 2020/187913, Nat. Commun. 2021). We will optimise this technology to select the most appropriate metabolites to target brain cancer cells and to chemically fine-tune their optical and physicochemical properties so that they can be formulated as hydrogels for topical administration in the brain. Importantly, the team involves established researchers with expertise in molecular imaging, medicinal chemistry, neurosurgery, and biomedical engineering. The team will have access to relevant human material for the optimisation and validation of the new chemical agents, including patient-derived glioblastoma cell lines from the CRUK Glioma Cellular Genetics Resource (GCGR) resource at UoE and human brain material resected at surgery (ethics already approved within the team). The team will build on the excellent environment at UoE in brain cancer research, which includes the CRUK Brain Tumour Centre of Excellence and the Edinburgh Tessa Jowell Brain Tumour Centre of Excellence, among others. Furthermore, the collaboration with HWU, an institution with international reputation in applied photonics and a growing portfolio in healthcare technologies, will accelerate the development of illumination devices suitable for the use of PDT in brain cancer surgery. The outcomes of this research will provide a solid foundation for future translational funding to support GMP manufacturing of optimal PDT agents and preclinical toxicology studies, with the view to design and implement a phase 0/1 investigation medicinal product for a exploratory first-in-human clinical study.