Rethinking repurposing: Developing cryogel technology to address glioblastoma recurrence through year-long local delivery of repurposed therapeutics

重新使用现有药物治疗脑癌。重新使用药物（也称为重新定位）是使用已被授权用于人类的现有药物治疗一种疾病/病症，然后使用它来治疗另一种病症的过程。这对于新的医学治疗来说是一个有吸引力的策略，因为药物开发和监管批准过程漫长，成本高，风险高。不幸的是，对于像高度侵袭性的胶质母细胞瘤这样的脑癌，这种重新利用的想法受到了严重的阻碍，因为大多数药物不能从血液中进入大脑。血脑屏障在正常生活中保护我们的大脑，阻止它们进入肿瘤。因此，目前的药物在实验室中可能对脑癌细胞非常有效，但无法在人体中达到目标。胶质母细胞瘤患者的预后很差-通常存活约14个月。尽管手术切除肿瘤（在大多数情况下），然后用单一药物进行放疗和化疗，但仍然存在一些癌细胞。这些细胞以多种形式出现，这意味着一种药物不太可能杀死所有细胞。不幸的是，剩余的细胞最终会导致肿瘤复发，最常见的是在原始肿瘤部位附近。因此，迫切需要新的治疗策略。为了这个项目，我们组建了一个具有各种研究背景的科学家团队来回答这三个关键问题：1）我们如何将重新设计的药物输送到肿瘤中？2)哪种药物或药物组合最好？3)我们如何计算出药物渗透到周围脑组织的程度，以清除残留的细胞？1)如何安全输送多种药物？我们建议制作一套柔软的海绵状材料，每种材料都装有不同的再利用药物。这些海绵（称为冷冻凝胶）可以插入手术过程中留下的空腔中。它们很容易被外科医生处理，并且非常柔软，可以很容易地压缩以填充空腔，而不会对大脑造成头痛的压力。通过使用一组海绵（每个海绵都装有不同的药物），手术团队可以选择这种模块化系统的组合，专门用于患者的最佳结果（所有癌症都略有不同）。我们的初步系统可以提供药物更长的时间（6个月）比其他系统的开发（天或周）。此外，我们的技术将是第一个可以重新填充的技术，为手术团队提供更大的灵活性，因为复发速度减慢，患者寿命更长。2）如何选择药物和组合？到目前为止，这是非常随意的，一些非常糟糕的药物选择。我们的团队将系统地筛选数千种潜在的药物，以找到：-那些最适合用于输送系统的药物，-那些对胶质母细胞瘤癌细胞造成最大伤害，但对健康大脑伤害最小的药物。我们希望这个屏幕的结果将完全改变我们对药物再利用治疗脑癌的看法。3）如何可视化药物渗透到大脑中？这是一个研究人员几乎没有答案的关键问题，因为它在技术上非常具有挑战性。我们的团队最近开发了一种新技术（首先在英国）用于成像药物在组织中的渗透，这将改变我们对药物输送后发生的事情的理解，从而更好地将动物数据转化为大型人脑。虽然胶质母细胞瘤是这项工作的一个明确目标，但我们相信我们的发现将高度适用于其他癌症，为研究人员提供直接将药物输送到靶部位所需的技术创新。

Repurposing existing drugs to treat brain cancer.Repurposing drugs (also known as repositioning) is the process of taking an existing medicine that is already authorised for human use in one disease/condition, and then using it to treat another condition. This is an attractive strategy for new medical treatments as the drug development and regulatory approval process is long, costly and high-risk. Unfortunately, for brain cancers such as the highly aggressive glioblastoma, this repurposing idea is severely hampered because most drugs cannot pass from the bloodstream to the brain. The blood-brain barrier, which protects our brains in normal life, hinders their passage to the tumour. Consequently, current drugs that may be highly effective against brain cancer cells in the laboratory, can't reach their target in a human.Glioblastoma patients have a poor prognosis - typically around 14 months survival. Despite surgical removal of the tumour (in most cases), followed by radiotherapy and chemotherapy with a single drug, some cancer cells remain. These cells come in many guises meaning that one drug is unlikely to kill them all. Unfortunately, the remaining cells ultimately cause tumour recurrence, most commonly near the original tumour site. Hence new therapeutic strategies are desperately needed.For this project we have assembled a team of scientists with a variety of research backgrounds to answer these three key questions:1) How can we deliver repurposed drugs to the tumour? 2) Which drug or drug combinations would be best to deliver? 3) How can we work out how far the delivered drug penetrates into the surrounding brain tissue to mop up those residual cells?1) How to deliver multiple drugs safely? We propose to make a set of soft, sponge-like materials, where each be loaded with a different repurposed drug. These sponges (called cryogels) could be inserted into the cavity left behind during surgery. They are easily handled by surgeons and are so soft that they compress very easily to fill the cavity without putting headache-causing pressure on the brain. By having a set of sponges (each sponge loaded with a different drug), the surgical team can choose combinations of this modular system specifically for the best outcomes in that patient (all cancers are slightly different). Our preliminary system can deliver drugs for far longer (6 months) than other systems in development (days or weeks). Furthermore, our technology would be the first that can be refillable, giving the surgical team even greater flexibility as recurrence is slowed and patients live longer.2) How to select drugs and combinations?Until now this has been done very arbitrarily, with some very poor drug selection. Our team would systematically screen thousands of potential drugs to find: - Those most suited for the delivery system, - Those that cause the most harm to the glioblastoma cancer cells, but least harm to the healthy brain. We hope that the results of this screen will completely change how we think about drug repurposing for brain cancers.3) How to visualise drug penetration into the brain?This is a key question that researchers have little answer for, as it is technically very challenging. Our team has recently developed a new technique (first in the UK) for imaging drug penetration in tissue, which will transform our understanding of what happens once the drug is delivered, allowing much better translation of animal data to the large human brain. Whilst glioblastoma is a clear target for this work, we are sure our findings will be highly applicable to other cancers, giving researchers the technological innovation required to deliver drugs directly to the target site.