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E-cadherin was observed compared to a luciferase control, suggesting better
suitability for systemic delivery. Capture within the lung microvasculature and sub-
sequent endothelial uptake were proposed by the authors as the mechanism of
delivery.
5.3.4
Aerosolised Formulations
It is anticipated that clinical translation will require inhalation technology based on
aerosols of dry powder formulation or solutions. Aerosols are by definition a gas-
eous suspension of fine solid particles or liquid droplets. The size and weight of
these particles or droplets determine their ability to follow the flow of inhaled air
through the airways.
The main parameter for linking particle or droplet size and weight in regard to
lung deposition is the aerodynamic diameter. This parameter takes into account
shape, roughness and porosity of the particles or droplets in an aerosol. The aerody-
namic diameter is the diameter of a unit density (1 g/cm
3
) sphere having the same
gravitational settling velocity as the particle being investigated. The mass median
aerodynamic diameter (MMAD) is the diameter at which 50% of the particle/drop-
let distribution by mass will have a larger or smaller diameter. In other words, if
deposition at a specific airway depth is required and is achieved at a given aerody-
namic diameter (e.g. 5 mm), then if the MMAD of an aerosol is 5 mm, then 50% of
the total aerosol mass will in principle deposit above the selected depth and 50%
will deposit below. This restricts nanoparticle diameter to a narrow size distribution
if deposition at a certain depth is required.
Investigation of MMADs of aerosols is typically carried out on cascade impac-
tors mimicking different airway depths. Particles with an aerodynamic diameter
between 1 and 5 mm are likely to reach the pulmonary regions, whereas larger par-
ticles will be deposited in the upper airways [
55
]. However, if particles become too
small, they are prone to being exhaled before depositing. This means solid nano-
particles, per definition, are in principle too small to be effectively deposited in the
lungs, and a large portion of these particles may end up leaving the lung again after
inhalation. There are two solutions to this problem. Either the particles are kept in
solution or they are attached to a carrier formulation which will facilitate deposition
at the required depth. Nanoparticles such as those consisting of polymers and
siRNAs are formed in solution, but subsequent drying by either spray drying [
107
]
or freeze drying [
108
] can produce particles retaining their silencing ability which
in terms of storage and stability of a therapeutic agent might be preferable compared
to a solution-based formulation.
Intratracheal administration in animal models has provided preclinical evalua-
tion of aerosolised siRNA formulations and is more cost-effective than inhalation
chambers. Nebulisers developed specifically for delivery of aerosols to animals
such as the “AeroProbe” from Trudell Medical and the “Microsprayer” from
Penncentury are examples of devices used for particle delivery directly to the
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