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Jonathan Pansieri

Amyloidosis: Detection using nanoparticles and original optical properties

Published on 19 May 2017

Thesis presented on May 19, 2017

Amyloidosis are diseases characterised by self-agregation of misfolded proteins in fibrillary forms, called amyloid fibrils. They are associated with many diseases, and their early diagnosis remains a clinical challenge. In this work, we show the targeting and the detection of amyloid fibrils, from in vitro to in vivo experiments in mice models, useful for early diagnostic of amyloidosis. For that purpose, we use multimodal nanoparticles, further functionalized with specific molecules against amyloid fibrils. This multimodality for imaging (fluorescence, MRI, PET) represent a breakthrough in modern medicine, to add structural and functional informations. After negative toxicity tests on various cell lines, these nanoparticles have been tested on three different amyloid fibrils, formed with amyloid β(1-42) peptide (Alzheimer’s disease), amylin (type II diabetes mellitus), or mutated Val30Met transthyretin (familial polyneuropathy). As it is shown by spectroscopy and surface plasmon resonance experiments, nanoparticles grafted with generic targeters (Pittsburgh compound B or a nanobody) target the three amyloid fibrils, with good affinity, whereas nanoparticles vectorised with peptides show specific targeting for amyloid β(1-42) or Val30Met mutated transthyretin, but with lower affinity. The targeting by nanoparticles have been confirmed ex vivo on pathological tissues with each amyloid burden, thanks to fluorescence microscopy. Generic nanoparticles have been injected in Alzheimer’s mice model, and the monitoring in vivo by IRM and post-mortem by optical microscopy supposed a targeting of amyloid β(1-42) aggregates in brain. Furthermore, we demonstrate the possibility to detect amyloid fibrils without labelling. Spectroscopic measurements show original, and specific optical properties of amyloid fibrils, around the UV-visible and the near infra-red regions. Interestingly, these properties are also observed on pathological tissues by ex vivo fluorescence microscopy, and in vivo ongoing analysis by photoacoustic imagery and real-time imaging seems to be very promising. By multimodality of non-toxic grafted nanoparticles or by intrinsic properties of amyloid fibrils suggesting completely non-invasive tests, these two strategies can be useful for early diagnostic of amyloidoses in humans.

Key words:
Amyloidosis, amyloid fibrils, nanoparticles