Biology Reference
In-Depth Information
Table 4.1
Intracellular barriers and methods to improve RNAi therapeutic delivery
Intracellular barrier
Delivery solution
References
Cell uptake and targeting
Folate-conjugated block copolymers
[
19
]
Aptamer-siRNA conjugates
[
20,
21
]
siRNA complex with protamine-antibody
fusion protein
[
22
]
siRNA-antibody conjugate
[
23
]
Cell-penetrating peptides
[
24-
27
]
Endosomal escape
Direct membrane translocation
[
28
]
Abrogate immune activation
[
29,
30
]
Proton sponge vectors
[
31-
40
]
pH-sensitive vectors
[
41,
42
]
Temperature-responsive pluronics
[
43
]
Photosensitizers
[
44
]
Fusogenic lipids
[
45
]
In fl uenza-derived fusogenic peptide diINF-7
[
46
]
Membranolytic peptides
[
47
]
Nuclear transport
Reducible copolypeptide containing nuclear
localization signal (NLS) to deliver siRNA
and pri-miRNA
[
11
]
RNAi release from vectors
Biodegradable poly(b -amino ester)s
[
48,
49
]
Degradable poly(lactide-
co
-glycolide)
[
50-
52
]
Carbamate-linked oligoamine-polyglycerol
[
53
]
Chitosan
[
54
]
Bioreducible polycations
[
55-
59
]
The following sections will describe the main intracellular barriers encountered by
the RNAi vectors during intracellular delivery. We will discuss current strategies applied
to overcome the individual barriers and to control the RNAi trafficking (Table
4.1
).
4.3.1
Cell Uptake and Targeting
Cell uptake is a key step required for successful delivery of RNAi therapeutics into
the target cells. Cell membrane consists of a hydrophobic phospholipid bilayer
embedded with various surface proteins. The physicochemical properties of this
biological barrier prevent direct translocation of the hydrophilic and negatively
charged RNAi molecules. Electrostatic complexation of RNAi molecules with vari-
ous cationic lipids and polymers is often employed to facilitate cell uptake. The
complexation results in a formation of particles with a net positive charge, which
helps to facilitate interaction with the negatively charged cell membranes and to
trigger internalization of the RNAi-containing particles via endocytosis.
Selective delivery of RNAi into specific cells can be achieved by direct binding
of the vectors to a variety of cell-type-specific receptors. For example, cholesterol-
siRNA conjugates can be efficiently internalized via receptor-mediated process by
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