Targeted nanoparticles for the detection and treatment of cerebral amyloid

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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.