Multi-functionalized nanoparticles for therapy and diagnosis of alzheimer's disease

Alzheimer Disease (AD) is the most common form of dementia among the older people and as the population ages, it is estimated to triplicate by 2040. Since an effective therapy and early diagnosis are not available at the date there is an urgent need to develop new methods and tools to treat this huge disease. The abnormal deposition of amyloid-beta peptides (Aβ) on brain tissues is one of the main neuropathological features of AD. Therefore, targeting of cerebral Aβ has been suggested for therapeutic and/or diagnostic purposes for the pathology. One of the main obstacle in the treatment of CNS diseases is the presence of the Blood-Brain Barrier (BBB) that selectively allows nutrients into the brain, while keeping out harmful components. Thus, the majority of drugs and contrast agents do not cross the BBB. Nanoparticle-mediated delivery represents one promising strategy to successfully treat CNS diseases, thanks to the unique properties of materials at the nanometer scale. Among the different nanoparticles (NPs), liposomes are attractive tools in biomedical applications thanks to their biocompatibility, non-immunogenicity, non-toxicity, biodegradability, high physical stability, versatility in surface functionalization. In this work of thesis liposomes have been functionalized with ligands able to bind Aβ and eventually inhibit its aggregation, or multi-functionalized with both ligands directed to Aβ and molecules (antibodies or peptides) enhancing the BBB crossing. These last ones have been attached on liposome surface by covalent or non-covalent coupling techniques (i.e. maleimide-thiol coupling chemistry or biotin-streptavidin conjugation). The ability of these NPs to bind Aβ has been assessed in vitro by using the Surface Plasmon Resonance (SPR) technology, as principal technique, and the ability to cross the BBB has been studied on a cellular model of barrier (hCMEC/D3). Within this PhD project, functionalized polymeric NPs have been also tested for their binding towards different aggregation forms of Aβ peptide.