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adsorptive surface area. Whilst in the upper respiratory tract, movement of apical
cilia on pseudostratified epithelium restricts interactions at the luminal surface.
Common to all mucosal epithelium is the close packing of adjacent cells separated
by tight junctions.
Material uptake across the epithelium can occur by transcellular or paracellular
pathways that are determined by the physicochemical characteristics of the mate-
rial. The main transcellular mechanism for nanoparticle transport across the epi-
thelium is adsorptive or cell-mediated endocytosis. Modification of material
properties or targeting specific sites can be used to maximise delivery across the
mucosa. It is generally accepted that the tight junctions restrict paracellular trans-
port of micro-nanoparticles; however, mucopenetration enhancers have been used
to facilitate transient opening of the junctions and mediate paracellular movement
of small molecules.
The migration of particles from local to systemic tissue relies on translocation
through the lymphatic or vasculature system and is dependent on the physicochemi-
cal properties of the material and the site. Disease pathogenesis dictates whether
there is a necessity for local and/or systemic delivery and should determine the
therapeutic strategy adopted.
5.3
Pulmonary Delivery
Direct access to a vast array of lung-associated diseases makes the lung an ideal
target for RNAi-based therapies. With a total surface area of 140 m
2
[
54
] , the pul-
monary route offers an attractive alternative to the invasive nature of intravenous
injections. The future clinical potential for pulmonary RNAi therapeutics holds
promise based on the large number of current inhalable traditional drugs and estab-
lished pulmonary delivery technologies provided by pressurised metered dose inhal-
ers (pMDIs) or dry powder inhalers (DPIs) [
55
] . The respiratory system also
provides an opportunity for drugs to reach the systemic circulation by uptake across
the thin epithelium of the alveoli.
Lung-associated diseases such as influenza and respiratory syncytial virus (RSV)
infection are prime candidates for siRNA therapy. The transient nature of gene
silencing is sufficient for acute viral disease treatment. Moreover, silencing of host
factors or conserved genes involved in viral replication could overcome the neces-
sity for seasonal drugs directed towards surface proteins that are susceptible to
mutational changes. Several host factors critical for viral replication [
56
] have now
been identified in influenza which provides a selection of novel targets for RNAi-
based therapies.
5.3.1
Considerations for Pulmonary Delivery of siRNA
The anatomy, physiology and immunology of the lung present a challenge to deliv-
ery of nanoparticle-based or naked siRNA. The lung is composed of the conducting
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