Biomedical Engineering Reference
In-Depth Information
Food and Drug Administration (FDA), CALAA-01 has entered a Phase I trial
for safety study to treat solid tumor cancers; this study is currently recruiting
participants.
In recent years, development of delivery vehicles capable of administering
siRNA efficiently and safely both in vitro and in vivo has been strongly needed.
An ideal carrier for systemic siRNA administration should have the following
properties: (a) be nontoxic and non-immunogenic for systemic human
administration; (b) condense siRNA efficiently; (c) maintain the integrity of
its content before reaching the target site and avoid rapid elimination from the
blood circulation; (d) reach diseased tissue, then specifically interact and
become internalized by target cells; and (e) dissociate in intracellular
compartments of the target cell to release the entrapped siRNA, making it
accessible to mRNA.
14
Although viral vectors have high transfection efficiency
in cancer cells or primary cells and sustained gene knockdown capacity,
15
safety concerns, including possible oncogenicity, inflammation, and immuno-
genicity, hamper their clinical application.
16,17
Hence, nanomedicne-based
vectors have been widely investigated as potential candidates for effective
siRNA delivery, such as polymeric micelles, quantum dots, liposomes,
polymer-drug conjugates, dendrimers, biodegradable nanoparticles, inorganic
nanoparticles, and other materials in the nanometer size range.
18
In this
chapter, we focus on the barriers impeding siRNA delivery and its therapeutic
effects, the development of different designs in polymeric micelles of siRNA,
their successful gene-silencing evaluation, and advanced applications in the co-
delivery of drugs and siRNA based on the micellar core-shell structure.
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7.2 Barriers to the Efficacy of siRNA Therapeutics
siRNA is a type of anionic and hydrophilic double-stranded small RNA. The
plasma membrane is a significant barrier to siRNA uptake. Despite their small
size, the hydrophilicity and negative charge of siRNA molecules prevent them
from readily crossing biological membranes (Figure 7.1). The intracellular
trafficking of siRNAs delivered by different reagents begins in early endosomal
vesicles. These early endosomes subsequently fuse with sorting endosomes,
which in turn transfer their contents to late endosomes. ATP-mediated proton
accumulation makes the endosomal compartments of cells significantly more
acidic (pH 5.0-6.2) than the cytosol or intracellular space (pH
#
7.4).
19
The
endosomal content is then relocated to the lysosomes, which are further
acidified
(pH
#
4.5)
and
contain
various
nucleases
that
promote
the
degradation of siRNAs.
20
In contrast to the direct accessibility of localized targets, many tissues can
only be reached through systemic administration in the bloodstream. siRNA
formulations for systemic application face a series of hurdles in vivo before
reaching the cytoplasm of the target cell.
21
Post-injection, the siRNA complex
must navigate the circulatory system of the body while avoiding kidney
filtration,
uptake
by
phagocytes,
aggregation
with
serum
proteins,
and
