Metabolic photosensitizers for photodynamic therapy of brain cancer.

用于脑癌光动力治疗的代谢光敏剂。

• 批准号: EP/W015706/1
• 负责人: Marc Vendrell
• 金额: $ 76.47万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FW015706%2F1
• 关键词: Metabolic; photosensitizers; photodynamic; therapy; brain

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.

胶质母细胞瘤是最具侵袭性的原发脑瘤，也是成年人潜在寿命损失最多的癌症。即使采用最佳手术方式，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，以及靠近不可触及结构的癌细胞的存在，这阻碍了肿瘤肿块的完全切除。这一未得到满足的临床需求推动了一种新技术的发展，以帮助外科医生在不损害健康组织的情况下优化肿瘤切除和消融。我们的技术建立在光动力疗法(PDT)的基础上，这是一种临床方法，通过光激活光敏剂(PS)引起的氧化应激来消融细胞。PDT目前还不能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98%以上的脑肿瘤复发在切除边缘几毫米以内。目前的PDT试剂(例如，5-氨基乙酰丙酸或5-ALA)作为治疗胶质母细胞瘤的PDT试剂有很大的局限性：1)5-ALA需要几个小时(2-5小时)才能“激活”，这一时间因患者而异，这使得很难为每个患者优化剂量；2)5-ALA的敏感性和选择性有限，这导致非靶点定位，无法达到最大限度的安全肿瘤切除。为了改进现有的PDT治疗胶质母细胞瘤的方法，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。这些新制剂的安全性和有效性将在患者的人体细胞和组织中进行检验。2-设计经济高效的设备，以安全地提供适当波长、功率和表面积覆盖范围的无毒光，供脑外科手术使用。这些标准化的系统将增加光动力疗法在外科干预中的可用性，使其成为一种更实用和更广泛地用于治疗胶质母细胞瘤的方法。总之，这种新的方法将允许临床医生以患者特有的方式优化肿瘤消融，最大限度地提高敏感性和特异度，同时将全身给药和靶外累积产生的副作用降至最低。交警。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，并从化学上微调它们的光学和物理化学性质，以便将它们制成水凝胶，用于大脑局部给药。重要的是，该团队包括在分子成像、药物化学、神经外科和生物医学工程方面具有专业知识的知名研究人员。该团队将获得用于优化和验证新化学制剂的相关人体材料，包括来自CRUK胶质瘤细胞遗传学资源(GCGR)的患者来源的胶质母细胞瘤细胞系，以及在手术中切除的人脑材料(团队内已经批准了伦理)。该团队将在UOE在脑癌研究方面的良好环境基础上再接再厉，其中包括CRUK脑瘤卓越中心和爱丁堡Tessa Jowell脑瘤卓越中心等。此外，与在应用光子学领域享有国际声誉并在医疗保健技术领域拥有越来越多产品组合的HWU的合作，将加快适合在脑癌手术中使用PDT的照明设备的开发。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GMP最佳PDT药物的制造和临床前毒理学研究，以期为探索性的第一次人类临床研究设计和实施0/1阶段研究药物。

项目成果

Miniaturized Chemical Tags for Optical Imaging

用于光学成像的小型化化学标签

• DOI: 10.1002/ange.202204788
• 发表时间: 2022
• 期刊: Angewandte Chemie
• 作者: Benson S

Miniaturized Chemical Tags for Optical Imaging.

• DOI: 10.1002/anie.202204788
• 发表时间: 2022-08-22
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Benson, Sam;de Moliner, Fabio;Tipping, William;Vendrell, Marc
• 通讯作者: Vendrell, Marc

Charting the Chemical Reaction Space around a Multicomponent Combination: Controlled Access to a Diverse Set of Biologically Relevant Scaffolds.

绘制围绕多组分组合的化学反应空间：对一组不同的生物相关支架的受控访问。

• DOI: 10.1002/anie.202303889
• 发表时间: 2023
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Nadal Rodríguez P

Charting the Chemical Reaction Space around a Multicomponent Combination: Controlled Access to a Diverse Set of Biologically Relevant Scaffolds

绘制围绕多组分组合的化学反应空间：对一组不同的生物相关支架的受控访问

• DOI: 10.1002/ange.202303889
• 发表时间: 2023
• 期刊: Angewandte Chemie
• 作者: Nadal Rodríguez P