Smart nanomaterials in the treatment of central nervous system diseases

The aim of this Ph.D. thesis has been the design, fabrication, and testing of nanotechnological solutions for the treatment of central nervous system diseases. In particular, different in vitro models of the so-called blood-brain barrier (BBB) were developed, and several nanomaterials were prepared and tested to assess their efficiency in biomedical applications. In the first part of the thesis, a brief introduction about the role of the BBB, the implication of reactive oxygen species, and the potential of nanotechnology in brain pathologies treatment has been given. In the second part of the thesis, two different newly developed BBB models have been proposed and discussed: the first one consisted of a bicompartmental dynamic in vitro system able to mimic within a single platform both brain vessel and brain cancer environments, while the second one, constituted by porous hollow capillaries realized through two-photon polymerization, represented the first dynamic in vitro BBB 1:1 scale system with brain capillaries. Both models have been presented in detail in terms of fabrication procedure, in vitro characterization with cells, mathematical modeling, and application in the testing of nanomaterials. In the third part of the thesis, three different antioxidant nanostructures have been presented. First nanostructured lipid carriers loaded with cerium oxide nanoparticles (NC-NLCs) were fabricated and exploited as a neuroprotective and pro-differentiative agent; NC-NLCs have been characterized in terms of size, morphology, zeta potential, stability, antioxidant capabilities, loading efficiency, biocompatibility and interaction with different cell lines. Moreover, the ability of NC-NLCs to cross an in vitro BBB model and to reach neuronal-like cells, to act a neuroprotective agent, and to stimulate neuronal differentiation has been investigated. Then nanostructured lipid carriers loaded with idebenone (IDE-NLCs) were realized and investigated as a possible countermeasure for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Again, a full material characterization similar to what presented for NC-NLCs has been performed. Moreover, IDE-NLCs antioxidant abilities were assessed on fibroblast-derived both from healthy subjects and both from patients affected by ARSACS. Lastly, polydopamine nanoparticles functionalized with a lipid coating (L-PDNPs) were analyzed as a multitasking tool for the treatment of neurological diseases. After a full material characterization, L-PDNPs activity on neuronal-like cells was assessed, demonstrating a high neuroprotective action, a protective effect against ROS-induced mitochondrial damages, and the ability to stimulate neuronal differentiation. Moreover, the photo-thermal conversion abilities of L-PDNPs was analyzed and exploited as a tool to control neuronal cell functions thanks to near-infrared laser irradiation.