Mucosal Delivery of RNAi Therapeutics - RNA Interference from Biology to Therapeutics - page 109

mucosal surfaces of the respiratory tract. These devices overcome the difficult
nature of the mouse breathing pattern and anatomy [ 109 ] and allow dose-response
studies to be conducted.
Substantial clinical evaluation of dry powder-based siRNA formulations is lack-
ing, although Alnylam ( http://www.alnylam.com , 2011) has used a handheld battery-
driven nebulising system ( http://www.paripharma.com , 2010) in their current phase
II RSV clinical trial with naked siRNAs. The promise of nanotechnology and the
advances with surface and particle engineering combined with recent advances in
inhaler technology hold promise for future inhalable siRNA-based particles.

5.4 Oral Delivery

Oral administration of therapeutics is considered the most favourable in terms of
cost-effectiveness, ease of administration and patient compliance. This route poten-
tially provides rapid systemic distribution of the drug [ 110 ] due to the enormous
adsorptive surface area (~200 m 2 ). Utilisation of this route depends on overcoming
the challenges of enzymatic degradation, mucus and epithelial penetration. Oral
administration of RNAi-based drugs offers great potential for both the treatment of
diseases occurring locally within the gastrointestinal (GI) tract, such as inflammatory
bowel disease (IBD), and to combat systemic pathologic conditions.

5.4.1 Considerations for Oral Delivery of siRNA

The GI tract possesses a specialised epithelium involved in the degradation of mac-
romolecules and assimilation of the obtained products while restricting the transport
of pathogens. Unfortunately, these processes often compromise the integrity and
absorption of therapeutics. In this respect, exposure to a highly active enzymatic
environment, extreme pH conditions and the existence of a selective-permeability
epithelial barrier are the main challenges for oral delivery of RNAi therapeutics.
Nucleases, highly abundant in pancreatic secretions, constitute the main enzymatic
barrier to nucleic acids. Moreover, the delivery system itself may be susceptible to
degradation by other enzymes present in the lumen (e.g. lipases, glycosidases or
proteases) or the microvillus (e.g. P450).
pH extremes along the GI tract ranging from 1 to 2 in the stomach to >7 at the
terminal part of the small intestine and colon may affect acid- or base-labile compo-
nents of the delivery system, although increased stability of nucleic acids under
these pH conditions can be achieved by chemical modifications [ 111, 112 ] or incor-
poration into delivery systems. Exploitation of the localised pH conditions could
offer an exciting strategy for site-specific release of siRNA using pH-sensitive car-
riers. Luminal pH determines the drug's ionisation degree that affects transcellular
passive diffusion and/or the interactions between the formulation components [ 84 ] .