FUS and surfactant-based nanocarriers: A combined strategy for nose to brain drug delivery

Brain drug delivery is hampered by the presence of the blood brain barrier and nanocarriers, administered by intranasal route, could represent an alternative and efficient strategy to improve drug localization in the Central Nervous System (CNS). The aim of this work is to design and characterize non-ionic surfactant vesicles (NSVs) and perfluorocarbon gas non-ionic surfactant based nanobubbles (VNBs) suitable for Nose to Brain Delivery (N2B). In particular, Pluronic F127, Span 85 and cholesterol have been employed to prepare NSVs and VNBs. Both systems have been characterized in terms of (a) hydrodynamic diameter, ζ-potential and morphology (b) vesicle bilayer feature (anisotropy), (c) physical-chemical stability and (d) fluorescent model probe release capability. VNBs have been also studied in terms of gas entrapment and acoustic efficiency. In addition, in order to understand optimal ultrasound (US) parameters to obtain in vitrostable cavitation, the acoustic pressure effect on VNBs fluorescent probes release kinetics was evaluated. The obtained results suggest that NSVs and VNBs show a hydrodynamic diameter suitable for N2B delivery. Moreover, in this study, we develop a new kind of protocol to evaluate an in vitroUS characterization of VNBs and our data suggest a stable and controlled probe release, encouraging the possibility to deliver VNBs in mixture with NSVs loaded neuroprotective drugs for brain delivery coupled to US obtaining stable cavitation. In this context, extracellular field recordings in specific area of hippocampus (CA1-CA3) have been carried out in order to assure that empty NSVs do not affect synaptic plasticity in the form of long-term potentiation, a molecular mechanism which underlies learning and memory.