Targeted nanoparticles for the detection and treatment of cerebral amyloid

描述（由申请人提供）：虽然中风是西方世界第三大死亡原因，但这种病理的早期诊断和治疗的临床进展相对有限。脑淀粉样血管病（CAA）是西方患者出血性中风的主要原因，与至少30%的出血性中风有关，并影响多达三分之一的75岁以上人群。脑淀粉样血管病（CAA）是出血性中风的重要病因，目前尚无诊断或选择性治疗的方法。CAA不能使用任何现有的成像技术在活着的患者中进行诊断，只能通过死后脑组织检查来检测。我们研究的长期目标是开发基于脂质体的纳米颗粒药物，用于多模式诊断和治疗应用，通过制造淀粉样蛋白结合的脂质体纳米颗粒，将核心封装的钆造影剂和治疗分子混合在一起，针对这种病理。在本项目中，我们建议通过开发含有高分辨率MRI显像剂的纳米颗粒来检测和治疗CAA，该纳米颗粒具有特异性靶向CAA中发现的淀粉样蛋白沉积物的配体，并包装有b-sheet断路器，可以选择性地治疗CAA病理。这种纳米颗粒的开发将为智能纳米技术平台奠定基础，该平台可以在活体患者中实现CAA的特异性、高分辨率可视化，其分辨率远远超过目前具有SPECT灵敏度的药物，同时允许在病理受影响的血管部位选择性地递送治疗药物。我们称之为淀粉样蛋白靶向成像纳米结构（ATINS）平台。我们提出以下具体目标：(1)通过优化这些纳米颗粒在体内的包装和递送来表征含有b-sheet破片的ATINS作为聚集抑制剂的作用；(2)证明ATINS可以作为一种治疗剂，用于同时进行高分辨率成像和治疗预先存在的CAA病理。这个项目的成功将产生一个多功能的纳米技术平台，作为未来药物的概念证明，可以同时成像和治疗活体患者的CAA病理，这项技术可以在CAA相关出血性中风领域产生巨大影响。

DESCRIPTION (provided by applicant): Although stroke is the third leading cause of death in the Western world, clinical advances in the early diagnosis and treatment of this pathology have been relatively limited. Cerebral amyloid angiopathy (CAA) is a major cause of hemorrhagic stroke in western patient populations, associated with at least 30% percent of bleeding strokes, and affecting as many as one third of all people over the age of 75. There are currently no methods to diagnose or selectively treat cerebral amyloid angiopathy (CAA), an important cause of hemorrhagic stroke, in living patients. CAA cannot be diagnosed using any currently existing imaging technology in living patients, and only detectable by postmortem examination of brain tissue. The long-range goal of our research is to develop liposome-based nanoparticle agents for multimodal diagnostic and therapeutic applications to target this pathology by creating amyloid-binding liposomal nanoparticles with a mixture of core-encapsulated gadolinium contrast agents and therapeutic molecules. In this project, we propose to detect and treat CAA by developing a nanoparticle containing high resolution MRI imaging agents with ligands that specifically target the amyloid deposits found in CAA, and packaged with a b-sheet breaker that can selectively treat CAA pathology. The development of this nanoparticle will establish the base for a smart nanotechnology platform that allows for specific, high-resolution visualization of CAA in living patients at a resolution that far exceeds current agents with the sensitivity of SPECT, while allowing for the selective delivery of therapeutics at pathologically-affected vascular sites. We call this platform Amyloid Targeted Imaging Nanostructure (ATINS). We propose the following specific aims: (1) to characterize the role ATINS containing b-sheet breakers as aggregation inhibitors by optimizing the packaging and delivery of these nanoparticles in vivo, and (2) to demonstrate ATINS can be used as a theranostic agent that can be used for simultaneous high-resolution imaging and treatment of pre-existing CAA pathology. Success in this project will result in a versatile nanotechnology platform that will serve as proof of concept for future agents to simultaneously image and therapeutically target CAA pathology in living patients, a technology that can have an enormous impact in the area of CAA-related hemorrhagic stroke. PUBLIC HEALTH RELEVANCE: There are currently no methods to diagnose or selectively treat cerebral amyloid angiopathy (CAA), an important cause of hemorrhagic stroke, in living patients. We propose to create a therapeutic agent that can both diagnose and treat this disease by using the well-known stealth liposome as a platform nanoparticle. We propose to modify the liposome for imaging and targeting pathogenic amyloid species associated with CAA, and to package therapeutic compounds within the nanoparticle that will selectively clear the CAA pathology. The development of this multifunctional platform will provide important scientific insights into the pathological role of CAA during aging, and serve as proof of concept for future therapeutic development.