Biology Reference
In-Depth Information
The clinical potential of nucleic acid-based drugs is restricted by the susceptibility
to serum nuclease degradation, rapid renal clearance and non-specific tissue accu-
mulation [ 4 ]. Furthermore, the macromolecular and polyanionic nature reduces
interaction and uptake across the cellular membrane required for recruitment into
the intracellular RNAi machinery. Improvements in both extracellular and intracel-
lular delivery are key to the therapeutic success of RNAi therapeutics. Chemical
modi fi cation [ 5 ] , conjugation [ 6 ] and incorporation into nanoparticle-based deliv-
ery systems [ 7, 8 ] are common strategies that have been employed to maximise
delivery [ 9, 10 ] .
The route of administration is an important determinant for successful RNA-
based silencing therapeutics. The administration route dictates both migratory path-
way and biological barriers the drug must undertake in order to reach its target.
Local administration to the mucosal surfaces lining the respiratory, gastrointestinal
and genitourinary tract is an attractive alternative to the intravenous route [ 11- 13 ] .
It is a non-invasive method that avoids hepatic and renal clearance associated with
the systemic route and allows direct access to regions that are the main portal of
entry and pathogenesis for many pathogens, inflammation and cancer.
Recent Phase II clinical trials with RNAi therapeutics delivered directly to the
lung [ 14 ] highlight the potential and support the use of the mucosal route.
This work describes pulmonary, oral, rectal and intravaginal delivery of RNAi
therapeutics focused on nanoparticle-based delivery of synthetic siRNA. Attention
will be given to the biological and physical barriers occurring at the mucosal sur-
faces that restrict uptake of luminal material. Strategies to improve mucosal pene-
tration will be discussed with a view to better design of mucosal delivery systems.
5.2
Mucosal Barriers
RNAi-based therapeutics must overcome the physical barrier of the mucus gel layer
and tightly packed epithelial cells combined with mucus capture and consequent
active clearance mechanism. Understanding these barriers and their evolutionary
differences can provide guidelines for siRNA-based therapy targeted at specific
mucosal sites. This section focuses on mucus and epithelial components relevant to
naked siRNA and nanoparticle-based siRNA delivery.
5.2.1
Mucus
Mucus is a hydrated protein gel which overlays the luminal surface at mucosal sites
and serves as a barrier between the external environment and the underlying tissue.
It lines the respiratory, gastrointestinal and genitourinary tracts, and eyes (Fig. 5.1 ).
Its role is to serve as a first line of defence against various pathogens [ 15 ] and toxins
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