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Periodic Report Summary 2 - NAD (Nanoparticles for therapy and diagnosis of Alzeimer disease)
Quality validation date:2013-02-01
Project context and objectives:
Over three million people in the European Union (EU) have Alzheimer disease (AD), with one in 20 people over 65, and one in five over 85. The objectives of this project are to use nanoparticles (NPs) specifically engineered for the diagnosis and therapy, even combined (theranostics), by targeting AD A peptide.
For this purpose, different NPs (liposomes, SLN, polymeric) will be multiple-functionalised with:
i) molecules interacting with the different pools and forms of A;
ii) molecules stimulating BBB crossing to reach the brain;
ii) PET or MRI contrast agents.
Artificial and cellular models will be used to improve and fine-tune NP binding to A, biocompatibility, BBB crossing and physical stability. The efficacy of NPs will finally be evaluated in rodent models of AD. The prediction is that NPs will range, detect, disaggregate, and remove brain A. Besides this action, NPs will interact with blood A, drawing out the excess of brain peptide by a 'sink' effect. NPs that can cross the BBB will be engineered as a side-product of the project, for potential applications in the pharmaceutical industry.
Ligands with high affinity in vitro for A peptide have been selected among naturally occurring small molecules (phosphatidic acid and its derivatives; curcumin) or synthesised within the consortium (antibodies).
Selected ligands for A peptide have been utilised for decoration of NPs, taking advantage of their amphiphilic nature or after chemical modification, either through a 'click' reaction with an azido group in the case of curcumin derivative, or via a cysteine-maleimide linkage in the case of antibodies.
The ability of NPs decorated with ligands to bind A has been demonstrated with SLN, liposomes or PEGylated polymeric NPs.
Different molecules, potentially able to cross the Blood Brain Barrier (BBB) have been identified (tat peptide, anti-TfR antibody, ApoE peptides) and linked to NPs, alone or in combination with A ligands. Experiments utilising in vitro BBB cellular models have shown the ability of such NPs to cross the barrier.
NPs functionalised for imaging have been synthesised, containing Iron oxides, or Gd or F, to be employed for MRI or PET. Assessment of their applicability has been checked in vitro and in vivo.
NPs functionalised to bind A and to cross the BBB showed to be biocompatible and stable in biological fluids. Moreover, they are able to prevent amyloid peptide aggregation and to rescue its toxicity in cultured cells. These results provide a proof-of-principle in vitro of their possible application for the treatment of AD.
In vivo experiments have shown that NPs functionalised to bind A and to cross the BBB, after injections in transgenic mouse models of AD are able to decrease serum A, the content of A oligomers in the brain and the amount of plaques in the brain.
The present project addresses the necessity to develop new therapeutic and diagnostic tools to cope with AD. The results of the project, carried out on a large set of cellular and animal models, will provide new chances for the treatment and the diagnosis of AD in humans; the combined use of therapy and diagnostics will allow the efficacy of therapy to be followed. The use of new diagnostic and therapeutic methods based on nanotechnology is one of the potential future answers to the immense societal and economic problems linked to AD. Future applications of the nanotechnology systems for AD treatment will facilitate progress towards a more effective and socially sensitive medicine and improve the quality of life for elderly. The results are also expected to have a positive long-term impact on a broad spectrum of the medical research landscape in Europe, by generating NP-based diagnostics and CNS-therapy systems for further basic and applied research in this complex medical area, thus reinforcing competitiveness of European industry.
Public dissemination activities will educate the public and allow feedback of the society towards the scientific community. It will be source of unbiased and objective information for physician and patient.
List of websites: http://www.nadproject.eu/
|Programme||Project reference||Project title|
|FP7-NMP||212043||Nanoparticles for therapy and diagnosis of Alzheimer disease|
Organization:UNIVERSITA' DEGLI STUDI DI MILANO-BICOCCA
Address: Department of Experimental Medicine
48, Via Cadore
Subject index:Medicine, Health, Biotechnology, Life Sciences
Subject descriptors:Pharmacy, pharmacology, Cell biology, Genetics, Immunology
Subject class:Biology, Medicine
Record control number:54440