Biomedical Engineering Reference
In-Depth Information
deliver to the same set of first-pass organs (liver, spleen, and lung)
when introduced intravenously. Alternatively, direct delivery into
sites such as the eye, skin, and respiratory tract has been used
with more success. Once delivery to the organ of interest has been
achieved, RNAi molecules must still make contact with target cells
and cross the cell membrane to gain access to the cytosol where
the RNAi machinery resides. Overcoming these delivery obstacles
has been, and will continue to be, challenging with many factors
to be considered for the delivery of small interfering RNA (siRNA).
Here we outline efforts to improve not only delivery but also RNAi
efficacy in the vaginal mucosa as a means to treat genital infections,
particularly virally-driven cervical cancer.
9.2
siRNA Delivery Systems: A Brief Overview
Systemic, intravenous, delivery has been the most widely investigated
delivery route thus far due to the ease of administration as well as the
rapid distribution to various tissue sites. However, it has historically
been considered the most complex route of delivery, due to the size,
charge, instability, and short half-life of injected siRNAs. This short
half-life is caused by renal clearance and endogenous ribonuclease
digestion [2]. These obstacles can be reduced by incorporating
siRNAs into particles and complexes or by chemically modifying the
RNA backbone. The chemical modification of the siRNA backbone
through introduction of phosphorothioate and 2
-O-methyl sugar
residues shows enhanced resistance toward degradation by exo-
and endonucleases in serum and tissue [3]. However, even modified,
naked siRNAs have poor cellular uptake due to their small size, net
negative charge, renal clearance, and hydrophilicity [4]. Therefore
a range of delivery vectors such as liposomes, polymers, and
nanoparticles have been developed to facilitate cellular absorption
as well as provide a degree of protection and increase systemic
circulation time.
′
9.2.1
siRNA Conjugate Delivery
One method for improved siRNA cellular uptake is through the use
of cholesterol conjugates. These siRNA-cholesterol conjugates have
been shown to exhibit improved pharmacokinetic profiles and longer
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