RNAi as New Class of Nanomedicines - Harnessing Biomaterials in Nanomedicine: Preparation, Toxicity, and Applications - page 168

Since siRNAs fall below the size threshold for renal filtration
and are rapidly cleared from the circulatory system, a variety of
approaches have been developed to promote their systemic delivery
in vivo . Direct conjugation of one or both of the siRNA strands with lipid
or cholesterol molecules improves both circulation time and cellular
uptake of these bioconjugates, and consequently gene silencing
[104, 138]. The improved cellular uptake of siRNAs is a result of cell
membrane permeability to these hydrophobic bioconjugates. Cell
penetrating peptides (CPPs) have also been conjugated to siRNAs
to enhance their cellular delivery. Short extensions with positively
charged amino acids of CPPS help their translocation across the cell
membrane and delivery of siRNAs directly to the cytoplasm. This
highly efficient cellular uptake of CPP-siRNA conjugates takes place
in a receptor-independent fashion [111].
Mixing the siRNAs with various delivery agents can increase their
circulation time either by exceeding the upper limit of the particle
size for renal clearance or by promoting their association with
serum proteins (e.g., serum albumin). A number of delivery carriers
have been developed for improved in vivo delivery of siRNA, which
are based on cationic nanoparticles [110], lipids, and liposomes [2,
155]. Negatively charged siRNA molecules spontaneously interact
electrostatically with cationic liposomes or cationic polymers.
The positively charged core of the delivery nanoparticle also
allows enhanced interactions with cellular membrane leading to
internalization via adsorptive pinocytosis [160].
Most of the approaches developed to date can be divided into
two major categories: non-specific accumulation and targeted
delivery. Non-specific delivery utilizes the bias of macromolecules
to accumulate in cancerous or inflamed tissues due to the increased
permeability of the blood vessels, and retention associated with
dysfunctional lymphatic drainage, an eff ect commonly known as
enhanced permeability and retention (EPR) [72, 105]. This EPR
eff ect has been employed to successfully deliver siRNAs against
KLF5 (a transcription factor that is known to play a role in tumor
angiogenesis) to solid tumors. siRNAs mixed with neutral lipids and
coated with polyethylene glycol (PEG) for increased retention time,
resulted in the knockdown of KLF5 and subsequent suppression of
both angiogenesis within tumors and tumor growth [157]. However,
if the cells do not efficiently internalize the siRNAs, accumulation of