Novel Targeted Nanoparticles for Amyloid Plaque Imaging

Alzheimer’s Disease, the most common form of dementia in the elderly is characterized by the presence of Amyloid Plaques in the hippocampus and cerebral cortex; these plaques are higher molecular weight agglomerates of the Amyloid- protein. While conclusive diagnosis of the disease still has to be done post mortem and the best ante mortem methodology remains a battery of neuropsychological tests, the recent approval by the FDA of Positron Emission Tomography (PET) agents that bind the plaques following an intravenous injection, promises to at least provide screening (ruleout) of the disease. Amyloid plaques are now understood to be “necessary” but not “sufficient” for full blown Alzheimer’s disease. Yet, the availability of these PET agents is limited, due to the same-day radiosynthesis and transportation requirements of these short-lived isotopes. We have therefore investigated stable contrast agents, for Magnetic Resonance Imaging, that similarly bind amyloid plaques and could provide ruleout capability. In 2009 we discovered that liposomes bearing an amyloid-plaque binding thioflavine derivative (Methoxy XO4) on their surface, avidly crossed the blood brain barrier (BBB), and bound plaques in a mouse model of the disease. The bound particles were detectable by ex vivo microscopy. We have, in the last 6 years, progressively improved on this platform, with new ligands, better T1 agents, and improved formulations of these nanoparticles, to enable true T1 MR imaging of amyloid plaques in mouse models of Alzheimer’s Disease. Further, we have used a variant of these particles, optimized for X-ray based computed tomography (CT) imaging, to evaluate the leakiness of the blood brain barrier, and shown that in aged mice, the BBB is actually quite leaky, consistent with the avid permeation of the amyloid-binding particles through the BBB. In this seminar, an overview of the development of this exciting new class of amyloid binding agents will be presented. Declaration of Conflict of Interest: Ananth Annapragada is a co-founder of Alzeca LLC, a for-profit company that has licensed much of the technology described in this presentation, and is developing it as a commercial product.