Nanotechnology-based therapy and diagnostics of brain diseases (NANOBRAIN)


Funded by: Ministero dell’Istruzione, Università e Ricerca (MIUR)  
Calls: Progetto Bandiera
Start date: 2012-01-01  End date: 2015-12-31
Total Budget: EUR 987.000,00  INO share of the total budget: EUR 273.647,00
Scientific manager: Ratto Gian Michele   and for INO is: Ferraro Pietro

Organization/Institution/Company main assignee: CNR – Istituto Nanoscienze

other Organization/Institution/Company involved:
CNR – Istituto per l’Officina dei Materiali IOM
CNR – Istituto di Bioimmagini e Fisiologia Molecolare

other INO’s people involved:
Grilli Simonetta
Cancio Pastor Pablo
Dinelli Franco
Miccio Lisa

Abstract: Brain tumors and neurodegenerative pathologies such as Alzheimer’s disease (AD) represent the major disorders of the central nervous system (CNS). The lack of reliable diagnostic markers and pharmacological therapies for these diseases is mainly ascribable to the blood-brain-barrier (BBB) that isolates the brain from the rest of the body. Consequently, most CNS-active agents are unable to reach the brain tissue in therapeutically active concentrations, and biomarkers of disease penetrate in very tiny amounts outside the BBB. In this context, nanotechnology is expected to play a pivotal role through the exploitation of (i) novel sensors for diagnosis and (ii) nano-sized carriers for drug delivery across the BBB. Here we promote the convergence between nanotechnology and neuroscience by fostering the collaboration between four top CNR institutes. This proposal will lead to advanced diagnostics of circulating biomarkers and nanoparticles-mediated treatment of brain tumours and AD.
The brain is biochemically and immunologically isolated from the body by the Brain Blood Barrier (BBB) a complex structure formed by the cells that form the vessel walls and the surrounding astrocytes. As result of this, most circulating factors are excluded from the brain parenchyma and, conversely, factors released in the brain extracellular space are not allowed to diffuse away from the Central Nervous System (CNS). This fact influences both the capacity of delivering drugs to the brain (only about 2% of the possible CNS therapeutic compounds can cross the BBB reaching their pharmaceutical targets) and the capacity of reading the presence of biomarkers of brain pathologies outside of the BBB. These facts have been known for long time and have strongly limited our capacity of early diagnostic and treatment of brain disease. In this project we will attempt to circumvent these limitations by novel tools for advanced sensing and drug delivery based on the paradigm of nanotechnology. These tools, will be brought to bear on two crucial issues of brain therapy: non-invasive early diagnosis of brain pathologies and the use of biodegradable nanoparticles (NP) for drug delivery to the brain.
Nanotech and Diagnostic.
Here we will use state of the art nanotechnologies for the label-free ultra-sensitive revelation of the binding between specific pathological markers and the sensor functionalized with appropriate antibodies. The sensing device and the associated microfluidic platform will allow to recogniza the biding of few thousands molecules and hopefully this extreme sensitivity will allow the recognition of the markers in fluids collected outside of the BBB.
We will target markers for Alzheimer disease (amyloid beta 1-42, total tau protein and P-Tau181P), and for Glioblastoma (Cathepsin-D and glial fibrillary acidic protein – GFAP). The partnership will explore different technologies of detections (WP 3) built on top of a common microfluidic platform optimized for the detection of small concentration of analytes dispersed in macroscopic volumes. Each technology will produce a proof of principle device that will be tested with a common set of benchmarks obtained from animal models of brain disease (WP 1).
Drug delivery.
Trafficking of NPs into and within the brain will be monitored in vivo by means of single particle tracking imaged by non linear microscopy. Here for the first time, we will obtain accurate kinetic data for processes such as the transport through the olfactory nerve, the passage through the BBB, the diffusion inside the brain parenchyma. Furthermore, we shall be able to evaluate in what extent the alteration of the BBB occurring at the core of glioblastoma influence the passage of NP in the tumour. These study will culminate in a proof of principle experiment in which we will target a glioblastoma implanted in the mouse brain with functionalised NPs. The combination of physiological, behavioural and chronic in vivo imaging will allow monitoring the tumour progression and response to the treatment.

INO’s Experiments/Theoretical Study correlated:
Thin Film Properties on the Nanoscale: from Oligomers to Polymer, from 2D Materials to Ferroelectrics
Ultrasonic Force Microscopy (UFM): Nanomechanics and Subsurface Detection