Biology Reference
In-Depth Information
Nanoshells and Quantum Dots), whilst organic nanoparticles include fullerenes,
dendrimers and virus-like structures. These new nanocarriers have been explored
for their use in a variety of applications such as drug delivery, imaging, photother-
mal ablation of tumours, radiation sensitisers, detection of apoptosis and sentinel
lymph node mapping [
27,
28,
42
]. An alternative strategy is construction of nano-
conjugates by attachment of moieties such as cholesterol to the siRNA to control the
systemic delivery. In choosing an appropriate nanocarrier construct for rapid and
effective clinical translation, one should consider the following criteria:
1. A carrier should be made from a material that is biocompatible, well character-
ised and can be easily functionalised.
2. A nanocarrier should exhibit high differential uptake efficiency by the target
cells or tissue.
3. A nanocarrier should be either soluble or colloidal in water and have an extended
circulating half-life to increase the likelihood of its effectiveness.
4. A nanocarrier should have a low rate of aggregation and a long shelf-life.
In delivering RNAi payloads, we can subdivide the delivery strategies based on
passive and active cellular targeting.
6.4.1
Passive Systemic RNAi Delivery
Passive delivery strategies are the most advanced (from a clinical standpoint) to
deliver RNAi payloads systemically. These strategies exploited the enhanced per-
meability and retention (EPR) effect (Fig.
6.1
) where leaky blood vessels and inef-
fective lymphatic drainage cause accumulation of macromolecules and nanoparticles
in close proximity of the tumour [
27,
43,
44
] .
Among the RNAi delivery strategies that utilise the EPR effect are the stable
nucleic acid-lipid particles (SNALP). SNALP is a ~100-nm non-targeted liposome
with low cationic lipid content that encapsulates siRNAs and is coated with a dif-
fusible polyethylene glycol-lipid (PEG-lipid) conjugate [
45,
46
] . The PEG-lipid
coat stabilises the particle during formation and provides a neutral and hydrophilic
exterior that prevents rapid systemic clearance. The lipid bi-layer composed of cat-
ionic and fusogenic lipids enables the internalisation of the SNALP and endosomal
escape while releasing the siRNA payload. Biodistribution study indicates that most
(28%) of the siRNAs carried by the SNALPs accumulated in the liver and only
0.3% in the lungs. Functional study of SNALPs encapsulated ApoB-siRNA has
shown significant reduction in ApoB mRNA levels. Despite the presence of cationic
lipids known to trigger toxicities [
24,
25
], studies in mice and non-human primates
did not reveal any adverse effects except for liver enzyme release. Based on these
results, a clinical trial is now been conducted to test the ability of SNALPs to deliver
siRNAs for liver cancer treatment. SNALPs encapsulating siRNA against the poly-
merase gene of the Zaire strain have been shown to protect guinea pigs from a lethal
challenge of the Ebola virus [
47
]. Other formulations of cationic liposomes, with
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