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

这个小企业创新研究（SBIR）第二阶段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。TBI很常见;全世界每年有超过1000万人脑部受伤，这是年轻人死亡和残疾的最常见原因。目前还没有药物可以限制受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持在那里，直到它完成工作，而较少的药物进入正常组织。这样，就有可能使用药物，虽然对脑损伤有益，但可能会对其他地方造成损害。这也使得使用新型药物成为可能，否则这些药物将无法到达大脑中的目标。如果该公司成功地将这项技术引入临床，它可能会使脑损伤患者更好，并为医疗保健系统节省大量资金。拟议的项目将开发一个高度有效的技术平台，用于急性脑损伤的定点药物输送。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作用。有针对性的交付可以避免这个问题。在第一阶段，该公司描述了一种新的肽CAQK，它专门将各种类型的有效载荷从全身给药递送到脑损伤部位。开发具有高亲和力和稳定性的该肽的改进变体对于确保该技术的最佳临床转化非常重要。本项目的目标是通过探索CAQK肽的不同修饰来优化递送平台，并使用化合物库的高通量筛选来搜索再现CAQK活性的化合物。该II期申请的结果将是一组稳定的、长循环的、高亲和力的肽和/或小分子化学模拟物，其可用于向受损的大脑靶向药物递送。最有前途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以提高疗效，减少副作用和易于管理的形式出现。

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.