Biomedical Engineering Reference
In-Depth Information
in a sequence-independent manner.
45
TLR7 and TLR8 were initially shown to
mediate the recognition of RNA viruses
48,49
and small synthetic antiviral
compounds referred to as imidazoquinolines.
50
It has been shown that TLR7 is
absolutely required for the induction of cytokines using the appropriate
knockout mice in murine immune cells in response to siRNAs.
42,43,51
siRNAs
can be recognized by human plasmacytoid dendritic cells (pDCs) through
TLR7
42,51,52
and human monocytes likely via TLR8.
52,53
TLR7 and TLR8
mediate the recognition of siRNAs in a sequence-dependent manner, and
RNA sequences including UG dinucleotides and the 59-UGU-39 motif are
preferentially recognized.
54,55
Thus, the sequence issue of siRNA-mediated
immune stimulation still needs to be further investigated.
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7.3 Polymeric Micelles for siRNA Delivery
To overcome the barriers to siRNA therapy, it is necessary to deliver siRNAs
by suitable systemic carriers to treat most cancers and other diseases. With
rapid advances in nanotechnology, many delivery systems have been
developed, including polymer-drug conjugates, polymeric micelles, dendri-
mers, liposomes, and inorganic particles with a size range of 1-1000 nm.
Polymeric micelles are nanosized particles that are made up of polymer
chains and are usually spontaneously formed by self-assembly in a liquid,
generally as a result of hydrophobic or ion pair interactions between polymer
segments. Micelles typically have a so-called core-shell structure. Polymeric
micelles as drug delivery systems were introduced in the early 1990s by
Kataoka's group by the development of doxorubicin-conjugated block
copolymer micelles.
56
They have been used for drug or gene delivery for
cancer therapy in preclinical and clinical studies.
Self-assembly of polymeric micelles starts as the concentration of the
polymer reaches the critical micelle concentration (CMC). Below the CMC, the
number of amphiphilic polymer molecules at the air/water interface increases
with increasing concentration; at the CMC, both the bulk and the interface
become saturated with monomers. Expulsion of ordered water molecules into
the bulk aqueous phase brings about micelle association, which is entropically
driven
57
as shown in Figure 7.2. The CMC of polymeric micelles can be as low
as 10
-6
M,
58
which increases the stability of the micellar structure with extreme
dilutions after intravenous administration to patients.
59
Polymeric micelles
possess other properties requested by ideal drug carriers, such as biodegrad-
ability, small particle size, high loading capacity, prolonged circulation, and
accumulation in tumors.
60
The characteristic size in the range of several tens to
hundreds of nanometers and the surrounding hydrophilic polymer layers
endow them with the ability to avoid undesirable foreign-body recognition by
the RES in biological entities and to achieve effective extravasation from the
bloodstream into tumors through the enhanced permeation and retention
(EPR) effect, resulting in high drug accumulation at the target site. On the
other hand, inner cores play a pivotal role in the stability of micelles as well as
