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provided by the environment found within the specific tissues or intracellular com-
partments. Indeed, several intracellular signals, such as low pH [
73,
74
] , glutathione
[
76
] , and speci fi c enzymes [
77
], have been used in the design of stimuli-responsive
polymeric nanocarriers. This section focuses on the design of multifunctional block
copolymers for a successful cytoplasmic delivery.
8.6.1
Stimuli-Responsive Systems
A variety of biochemical environments encountered by the micelles during the path
to the diseased tissue can be utilized to promote physicochemical changes in poly-
meric nanocarriers [
78,
79
]. For instance, the pH in the bloodstream is ~7.4 while
~6.5 in the early endosomes and 5.5 in the late endosomes, rising to 7.2 in the cyto-
plasm [
80
]. These pH changes allow the integration of an endosomal escape func-
tion to the polymer, and thus to the micelle, by utilizing polymers possessing acidic
pH sensitivity.
Surprisingly, simple polycations such as PEI have presented significant endo-
somal escape due to low p
K
a
amines that undergo protonation in an acidic environ-
ment. The mechanism through which low p
K
a
amines promote endosomal escape is
the “proton sponge effect,” in which the protonation of amines in the endosome
stimulates the influx of protons and chloride ions into this compartment, increasing
the osmotic pressure that results in the disruption of the compartment [
81
] . Although
the “proton sponge effect” is the theory most accepted in this case, its effectiveness
is under debate [
82
]. Concerns regarding PEI cytotoxicity have restricted its clinical
use; therefore, new biodegradable PEI derivatives for siRNA delivery are being
designed to enhance transfection efficacy using substitution of degradable moieties
and copolymers [
83,
84
]. Interestingly, Park and colleagues developed a siRNA vec-
tor comprising PEI grafted to hyaluronic acid (HA) via a disulfide linkage (PEI-
SS-HA). Described as a nontoxic vector, specific cellular uptake by the HA receptor
through endocytosis is observed. In addition, intratumoral injection of this complex
incorporating VEGF siRNA significantly suppressed subcutaneous tumor growth
through the anti-angiogenic effect with decreased VEGF mRNA and protein [
37
] .
A comprehensive study done by our group [
80,
85-
87
] has shown that aligning
the aminoethylene structure (the main component of PEI) in the side chain of a
polymer strand can significantly decrease the polycation cytotoxicity by generating
pH sensitivity. As observed in PAsp(DET) and PAsp(TEP) (PAsp(TEP): poly[
N
-(
N
-
{
N
-[
N
-(2-aminoethyl)-2-aminoethyl]-2-aminoethyl}-2-aminoethyl)aspartamide]),
a monoprotonated structure is present at pH 7.4 while the drop to pH 5.5 allows the
formation of a diprotonated structure in the 1,2-diaminoethane unit, which is essen-
tial for the endosome-selective membrane destabilization effect. This selective pro-
tonation of the polymer in the endosomes allow efficient but less toxic endosomal
escape of the micelles (Fig.
8.7
).
Stimuli-responsive polymers not only allow enhanced endosomal escape, but
also provide efficient siRNA release from the micelles in the cytoplasm. A review
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