Biomedical Engineering Reference
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pression in macrophages following intraperitoneal administration
of chitosan-siRNA nanoparticles for downregulation of local and
systemic inflammation [23, 24]. Additionally, chitosan's ability
to deliver siRNA across the mucosal epithelium, as seen with
intranasal administration of chitosan-siRNA formulations to the
lung [25, 26], makes it an attractive delivery platform for a variety of
mucosal-based diseases.
Another polymer based delivery system that has received
attention recently is PLGA, an FDA-approved, biodegradable
polymer that is inherently stable in biological systems. However,
this characteristic becomes problematic for endosomal escape and
release of siRNA into the cell cytoplasm [27].
9.2.4
Lipid-Based Delivery Particles
Complexing siRNAs into lipoplexes is an alternative method used
to assist systemic delivery due to liposomal protection of the siRNA
from degradation, reduced renal clearance, and superior uptake
abilities [28]. Cationic lipid vectors have been used with success in
delivering siRNAs for local application [29], but their use in systemic
delivery is limited due to their aggregating properties in serum [30].
Therefore, alternate strategies for systemic lipid delivery have been
investigated, including the use of polyethylene glycol (PEG) and
neutral lipids, which exhibit superior pharmacokinetic profiles.
Utilising PEG and neutral lipids for encapsulation of siRNA molecules
into liposomes has been highly successful in systemic knockdown
studies [15, 31-33].
A critical factor that influences liposome/siRNA biodistribution
is particle size. Particles smaller than 100 nm are required to con-
verse the small liver endothelium and access hepatocytes.
Nanoparticles that have a slightly larger diameter of 100-200 nm
accumulate in tumours due to the enhanced permeability and
retention (EPR) effect. Nanoparticles of this size penetrate into
tumours mainly due to a disorganised endothelium and are retained
partially due to the lack of lymphatic drainage [34].
In 2005, a scalable method of formulating spontaneous PEGy-
lated lipid particles or stable nucleic acid lipid particles (SNALPs)
was developed by Protiva Biotherapeutics [35]. PEGylated siRNA-
loaded cationic lipid systems have been widely employed for systemic
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