Biomedical Engineering Reference
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the extracellular level (ca.2mM). 99 Therefore, different disulfide-linked redox
delivery systems have been designed for intracellular siRNA release triggered
by GSH in tumor cells, classified mainly under two categories of siRNA
conjugates with disulfide linkages and micelles with disulfide crosslinked cores
(Figure 7.8).
siRNA conjugates can improve the in vivo pharmacokinetics, increase the
half-life, and increase the delivery efficiency of siRNA, 101-104 but these
chemical modifications affect its activity and specificity. Therefore, ''revers-
ible'' siRNAs have been developed by attaching siRNAs to polymers via
disulfide linkages. Park's group successfully developed polyelectrolyte complex
(PEC) micelle delivery systems for antisense oligonucleotides (ODN) based on
the chemical conjugation of ODN to PEG, 105,106 and they extended the ODN
PEC micelle strategy to a siRNA delivery system for effective silencing of the
VEGF gene in human prostate carcinoma cells. VEGF siRNA was conjugated
to PEG via a disulfide linkage in order to be cleaved in a reductive cytosolic
environment. Branched polyethylenimine (PEI) was used as a cationic core
condensing agent (Figure 7.9). 107 The PEC micelles self-assembled to form a
core-shell structure via electrostatic interactions between the two oppositely
d n 4 y 3 n g | 8
Figure 7.8
Intracellular siRNA release can be triggered by reductive cleavage of
disulfide linkages in redox-sensitive polymeric micelles. GSH is a thiol-
containing tripeptide and its intracellular concentration is 1000 times
higher than the extracellular level.
 
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