The olfactory region of the nasal cavity directly links
the brain
to the external environment, presenting a potential direct route to
the central nervous system (CNS). However, targeting drugs to the
olfactory region is challenging and relies on a combination of drug
formulation, delivery device, and administration technique to navigate
human nasal anatomy. In addition, in vitro and in vivo models utilized
to evaluate the performance of nasal formulations do not accurately
reflect deposition and uptake in the human nasal cavity. The current
study describes the development of a respirable poly(lactic-co-glycolic acid) nanoparticle (PLGA NP) formulation, delivered
via a pressurized metered dose inhaler (pMDI), and a cell-containing
three-dimensional (3D) human nasal cast model for deposition assessment
of nasal formulations in the olfactory region. Fluorescent PLGA NPs
(193 ± 3 nm by dynamic light scattering) were successfully formulated
in an HFA134a-based pMDI and were collected intact following aerosolization.
RPMI 2650 cells, widely employed as a nasal epithelial model, were
grown at the air–liquid interface (ALI) for 14 days to develop
a suitable barrier function prior to exposure to the aerosolized PLGA
NPs in a glass deposition apparatus. Direct aerosol exposure was shown
to have little effect on cell viability. Compared to an aqueous NP
suspension, the transport rate of the aerosolized NPs across the RPMI
2650 barrier was higher at all time points indicating the potential
advantages of delivery via aerosolization and the importance of employing
ALI cellular models for testing respirable formulations. The PLGA
NPs were then aerosolized into a 3D-printed human nasal cavity model
with an insert of ALI RPMI 2650 cells positioned in the olfactory
region. Cells remained highly viable, and there was significant deposition
of the fluorescent NPs on the ALI cultures. This study is a proof
of concept that pMDI delivery of NPs is a viable means of targeting
the olfactory region for nose-to-brain drug delivery (NTBDD). The
cell-based model allows not only maintenance under ALI culture conditions
but also sampling from the basal chamber compartment; hence, this
model could be adapted to assess drug deposition, uptake, and transport
kinetics in parallel under real-life settings.