Metabolic photosensitizers for photodynamic therapy of brain cancer.

胶质母细胞瘤是最具侵袭性的原发性脑肿瘤，也是成年人潜在寿命损失最多的癌症。即使采用最佳手术，中位生存期也只有15个月左右。这主要是由于胶质母细胞瘤的浸润性质和癌细胞靠近不可触及的结构的存在，这阻碍了肿瘤块的完全切除。这种未满足的临床需求推动了新技术的开发，以帮助外科医生优化肿瘤切除和消融，而不损害健康组织。我们的技术建立在光动力疗法（PDT）的基础上，这是一种通过光激活光敏剂（PS）引起的氧化应激来消融细胞的临床方法。PDT目前无法用于胶质母细胞瘤的常规治疗，但它可以用于靶向接近重要结构的残留肿瘤细胞，因为超过98%的脑肿瘤在切除边缘的几毫米内复发。目前的PDT药剂（例如，5-氨基乙酰丙酸或5-ALA）作为用于胶质母细胞瘤消融的PDT试剂具有主要局限性：1）5-ALA需要几个小时（2至5小时之间）是“活跃的”，并且该时间在患者之间变化，使得难以针对每个患者优化给药; 2）5-ALA具有有限的灵敏度和选择性，这导致脱靶定位和无法实现最大安全的肿瘤切除。为了改善用于治疗胶质母细胞瘤的现有PDT方法，我们的目标是：1 -开发新的PS，可以在手术干预期间局部给药后几分钟内选择性地进入脑癌细胞。这些新药物的安全性和有效性将在患者的人体细胞和组织中进行检查。2-设计具有成本效益的设备，用于安全输送适当波长、功率和表面积覆盖的无毒光，用于脑外科手术。这些标准化的系统将提高PDT在外科干预中的可用性，使其成为治疗胶质母细胞瘤的更实用和更广泛使用的方法。总而言之，这种新方法将允许临床医生以患者特定的方式优化肿瘤消融，最大化灵敏度和特异性，同时最小化源自全身给药的副作用，该提议建立在PI的团队开创的SeNBD技术（专利申请：WO 2020/187913，Nat. Commun. 2021年）。我们将优化这项技术，以选择最合适的代谢物来靶向脑癌细胞，并对它们的光学和物理化学性质进行化学微调，以便它们可以配制成水凝胶，用于脑中的局部给药。重要的是，该团队包括具有分子成像，药物化学，神经外科和生物医学工程专业知识的知名研究人员。该团队将获得相关的人类材料，用于优化和验证新的化学试剂，包括来自UoE的CRUK胶质瘤细胞遗传资源（GCGR）资源的患者源性胶质母细胞瘤细胞系和手术切除的人脑材料（团队内部已经批准了伦理）。该团队将建立在UoE脑癌研究的优良环境，其中包括CRUK脑肿瘤卓越中心和爱丁堡Tessa Jowell脑肿瘤卓越中心等。此外，与HWU（一家在应用光子学方面享有国际声誉的机构，以及不断增长的医疗保健技术组合）的合作将加速开发适合在脑癌手术中使用PDT的照明设备。这项研究的结果将为未来的转化资金提供坚实的基础，以支持最佳PDT药物的GMP生产和临床前毒理学研究，以期设计和实施用于探索性首次人体临床研究的0/1期研究药品。

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.