Mucosal Delivery of RNAi Therapeutics - RNA Interference from Biology to Therapeutics - page 116

5.7 Future Perspectives

Mucosal delivery of RNAi therapeutics is an exciting approach that is set to prog-
ress rapidly building on encouraging clinical studies. The relative ease of access to
surfaces common to pathogen, cancer and inflammatory disease promotes their use.
Local delivery avoids the necessity to install “stealth” characteristics required for
systemic delivery that reduces the complexity of design that has manufacturing,
cost and clinical approval benefits. The restricted entry, however, encountered by
macromolecules across mucosal barriers still requires delivery strategies to improve
penetration. In this context, nanoparticles rather than naked forms seem the most
promising. Research to identify surface characteristics that promote mucus penetra-
tion including hydrophilic coats is set to continue, whilst coatings that mimic patho-
gens evolved to penetrate the mucosa is an interesting approach. Detailed studies of
nanoparticle penetration in mucus and changes in the mucus morphology in response
to mucopenetrative materials are a future trend. Variations in mucus characteristics
at different sites and disease states are an important consideration in the design of
the delivery strategy. The polyplex systems composed of siRNA and cationic poly-
mers such as chitosan could proceed rapidly into clinical trials due to their simplis-
tic design and mucoadhesive and mucopermeable properties. A current trend is to
identify new biopolymers to improve mucosal delivery and expand the selection of
available materials.
Recent attention has been directed towards oral formulations focused on treat-
ment of inflammatory diseases of the gastrointestinal tract. Anti-inflammatory
effects in IBD preclinical models using particle formulations suggest that IBD will
be a primary candidate for clinical translation. The development of bioresponsive
particles or coatings composed of pH-sensitive materials, employed for other drug
types, will offer the possibility for localised site-specific delivery utilising the dif-
fering pH found throughout the GI tract. The necessity for particle disassembly
needed for siRNA incorporation into the cellular RNAi machinery calls for intra-
cellular release mechanisms [ 131, 132 ]. Reducible disulphide links that are cleaved
in the cytoplasm is a strategy, but cost may preclude clinical translation. In contrast
to the necessity for stable particles in the circulatory environment, mucosal delivery
allows the use of less stable systems that could facilitate siRNA release.
The ability of nanoparticles to translocate the mucosa and enter systemic circula-
tion is set to be exploited to elicit local and systemic silencing effects often needed
to match pathogenesis. This, however, will require further modifications to avoid
serum-induced aggregation and hepatic clearance. The success of this approach will
depend on the technologies currently pursued for systemic nanoparticle delivery. To
this end, improving nanoparticle delivery across lymphoid tissue as a route for sys-
temic delivery is set to continue with identification of new targeting approaches
running in parallel.
In addition to improved delivery systems, siRNA design is an important consider-
ation relevant to all routes of administration. Some of the initial siRNA-mediated
antiviral effects were seemingly attributed to non-specific induction of innate