In vivo targeting and multimodal imaging of cerebral amyloid-ß aggregates using hybrid GdF3 nanoparticles.

ABSTRACT

Aim: To propose a new multimodal imaging agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease. Materials & methods: A new generation of hybrid contrast agents, based on gadolinium fluoride nanoparticles grafted with a pentameric luminescent-conjugated polythiophene, was designed, extensively characterized and evaluated in animal models of Alzheimer's disease through MRI, two-photon microscopy and synchrotron x-ray phase-contrast imaging. Results & conclusion: Two different grafting densities of luminescent-conjugated polythiophene were achieved while preserving colloidal stability and fluorescent properties, and without affecting biodistribution. In vivo brain uptake was dependent on the blood-brain barrier status. Nevertheless, multimodal imaging showed successful Aß targeting in both transgenic mice and Aß fibril-injected rats.

The design and study of a new contrast agent targeting amyloid-ß (Aß) plaques in Alzheimer's disease (AD) is proposed. Aß plaques are the earliest pathological sign of AD, silently appearing in the brain decades before the symptoms of the disease are manifested. While current detection of Aß plaques is based on nuclear medicine (a technique using a radioactive agent), a different kind of contrast agent is here evaluated in animal models of AD. The contrast agent consists of a nanoparticle made of gadolinium and fluorine ions (core), and decorated with a molecule previously shown to bind to Aß plaques (grafting). The core is detectable with MRI and x-ray imaging, while the grafting molecule is detectable with fluorescence imaging, thus allowing different imaging methods to be combined to study the pathology. In this work, the structure, stability and properties of the contrast agent have been verified in vitro (in tubes and on brain sections). Then the ability of the contrast agent to bind to Aß plaques and provide a detectable signal in MRI, x-ray or fluorescence imaging has been demonstrated in vivo (in rodent models of AD). This interdisciplinary research establishes the proof of concept that this new class of versatile agent contrast can be used to target pathological processes in the brain.