SBIR Phase II: A Novel Platform to Enable Directed Delivery of Therapeutics into Brain Injuries

这个小型企业创新研究(SBIR)第二阶段的项目是开发精确引导的药物或诊断化合物输送到创伤性脑损伤(TBI)的损伤部位。颅脑损伤很常见，每年全球有1000多万人受伤，是年轻人最常见的死亡和残疾原因。目前还没有药物可以限制损伤后肿胀和炎症对大脑的额外损害，或者帮助修复大脑。该公司的技术允许人们将药物引导到受伤的大脑，并将其保留在那里，直到它完成工作，而进入正常组织的药物较少。这样，就有可能使用虽然对脑损伤有益，但可能在其他地方造成损害的药物。它还使使用新类型的药物成为可能，否则这些药物将无法达到大脑中的目标。如果该公司成功地将这项技术引入临床，可能会让脑损伤患者变得更好，也可能为医疗系统节省大量资金。拟议的项目将开发一个高效的技术平台，用于急性脑损伤的现场药物输送。神经保护剂在临床试验中失败的主要原因是缺乏特异性和治疗的剂量限制效应。定向投放可以绕过这个问题。在第一阶段，该公司描述了一种新型多肽CAQK，它通过全身给药专门将各种类型的有效载荷输送到脑损伤部位。开发这种多肽的高亲和力和稳定性的改进变体对于确保这项技术的最佳临床翻译非常重要。本项目的目的是通过探索CAQK多肽的不同修饰来优化递送平台，并利用高通量筛选化合物文库来寻找再现CAQK活性的化合物。这一第二阶段应用的结果将是一组稳定的、长时间循环的、高亲和力的多肽和/或小分子化学模拟物，可用于将药物定向输送到受损的大脑。最有希望的化合物将在脑损伤的动物模型中得到验证。脑损伤治疗的变革性进展应以提高疗效、减少副作用和易于给药的形式出现。

This Small Business Innovation Research (SBIR) Phase II project is to develop precision-guided delivery of drugs or diagnostic compounds to the site of damage in traumatic brain injury (TBI). TBI is quite common; every year, over 10 million people worldwide injure their brain, and it is the most common cause of death and disability in young people. There are currently no drugs available that would limit the additional damage to the brain from swelling and inflammation after the injury or help repair the brain. The company's technology allows one to guide a drug to the injured brain and keep it there until it has done its job, while less of the drug goes to normal tissues. This way, it will be possible to use drugs that, while beneficial in brain injury, may do damage elsewhere. It also makes it possible to use new types of drugs that would otherwise not reach their target in the brain. If the company is successful in bringing this technology to the clinic, it may make brain injury victims better, and significant savings to the healthcare system may also be obtained. The proposed project will develop a highly efficacious technology platform for site-specific delivery of drugs to acute brain injury. The main reasons for the failure of neuro-protective agents in clinical trials are lack of specificity and the dose limiting effects of the therapy. Targeted delivery can circumvent this problem. In Phase I, the company described a novel peptide, CAQK, which specifically delivers various types of payloads to sites of brain injury from systemic administration. Developing improved variants of this peptide with high affinity and stability is important in ensuring optimal clinical translation of this technology. The objective of this project is to optimize the delivery platform by exploring different modifications of the CAQK peptide, and to use high throughput screening of chemical compound libraries to search for compounds that reproduce the CAQK activity. The outcome of this Phase II application will be a panel of stable, long-circulating, high affinity peptides and/or small molecule chemical mimetics that can be used for targeted drug delivery to injured brain. The most promising compounds will be validated in animal models of brain injury. Transformative advances in brain injury treatment in the form of increased efficacy, reduced side effects, and ease of administration should ensue.