Biomedical Engineering Reference
In-Depth Information
suppression efficiency of the complex of the R3V6 peptide with siVEGF was
similar to that of the siVEGF/PEI25k complex.
76
Besides synthetic polymers, natural polymers are also utilized in siRNA
therapy. Spermine is a tetraamine involved in cellular metabolism and present
in all eukaryotic cells.
77
Hyaluronic acid (HA), a major constituent of the
extracellular matrix, is a naturally occurring non-sulfated glycosaminoglycan
(GAG) polysaccharide composed of N-acetyl-
D
-glucosamine and
D
-glucuronic
acid,
78
and its receptors such as CD44 and RHAMM are abundantly presented
in tumor cells.
79-81
Shen et al. developed a target-specific siRNA carrier using
hydrophobized hyaluronic acid-spermine conjugates (HHSCs).
82
The poly-
mers were able to effectively bind siRNA, self-assemble into micelles, protect
siRNA from degradation by nucleases, and release complexed siRNA
efficiently in the presence of low concentrations of polyanionic heparin.
HHSCs demonstrated improved transfection efficiency in an HA receptor
(CD44) overexpressing SGC-7901 cells compared to polyethylenimine with a
high molecular weight of 25 000 Da (PEI 25k) and Lipofectamine due to HA
receptor-mediated endocytosis of the complex.
83
d
n
4
y
3
n
g
|
8
7.3.2 Smart Responsive Micelles for siRNA Delivery
Micelle-based siRNA vehicles can passively accumulate in solid tumor tissues
owing to the EPR effect and thus improve siRNA therapeutic efficiency.
However, the concentration of active siRNA within cancer cells is often
insufficient due to the inefficient release of siRNA from the micelles into the
cytoplasm, resulting in a requirement for higher doses. One promising
approach to improving efficacy is to develop responsive carrier systems that
can release loading agents triggered by intracellular stimuli, such as pH
84
or
glutathione.
85,86
On reaching the targeted tumor, such carriers can be
subsequently provoked by these stimuli to release siRNA after internalization,
hence inducing aggressive activity within tumor cells and leading to maximal
therapeutic efficacy with reduced side effects.
7.3.2.1 pH-Responsive Polymeric Micelles
Once siRNA is endocytosed, the predominant fate is enzymatic degradation in
the lysosome and extracellular clearance.
87
Escape from the endosomal
compartment is believed to be a major rate-limiting step for many delivery
approaches.
88
In order to circumvent this fate, several pH-sensitive polymers
have been employed to enhance endosomal escape, including block copoly-
mers, conjugates, and dendrimers. The high efficiency of siRNA delivery by
protonable cationic polymers is mainly attributed to their high buffering
capacity, which has been hypothesized to mediate endosomal release by acting
as ''proton sponges'',
88
as shown in Figure 7.5. Proton absorbance by
buffering polymers prevents acidification of endosomal vesicles, thereby
increasing the ATPase-mediated influx of protons and counterions. Increased
