Biomedical Engineering Reference
In-Depth Information
Stealth carriers, such as HPMA
104
and pegylated particles, cannot diffuse
through the lysosomal membrane and thus can be retained in the lysosomes for
a long time. For instance, PEG-PCL particles were found confined in
lysosomes.
105
Thus, they must be functionalized with lysosomal membrane-
destabilizing polymers such as PPAA,
99,100
pH-dependent fusogenic pep-
tides,
106,107
or cationic polymers such as polyethylenimine (PEI)
108
or
histidine-rich peptides or polymers.
109
For cationic polymers or peptides, on
the other hand, it is important first to mask their cationic charges (from
primary and secondary amines) at physiological pH, so the carriers can be used
for i.v. administration. However, once inside the tumor lysosome, the cationic
charges are recovered to lyze the lysosomal membrane for escape. Such a
''negative-to-positive charge-reversal'' method makes the carrier stealthy in
circulation, but enables endosomal lysis, once in lysosomes.
108,110
Removal of a cleavable PEG layer can also allow lysosomal escape.
111
For
instance, a PEG-cleavable lipid, via an acid-labile vinyl ether linker, was used
for pegylation of (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) (DOPE)
liposomes. At acidic lysosomal pH the vinyl ether linker hydrolyzed and the
PEG layer was removed from the DOPE liposomes, enabling DOPE, which
has excellent fusogenic capacity, to fuse with the lysosomal membrane for
escape.
112
Disulfide linkages were also used to detach PEG and make the drug-
loaded carriers quickly escape from the endosomes.
113
After the particles were
internalized by cells and trapped by endosomes, the PEG layer was removed.
The exposed particles interacted with the endosomal membrane, increased
the endosomal pressure, or both, resulting in destruction of the endosomal
membrane to enable effective endosomal escape.
113
Most carriers reaching the cytoplasm have already experienced an initial
burst release and are in a slow, diffusion-controlled drug release process, e.g.
nanoparticles with cores made of solid glassy polymers such as PCL or
polylactide (PLLA).
114
According to Eq. 1 (see Figure 3.7), such a slow drug
release profile may not be able to lead to a high [D] lethal to cancer cells. Thus,
carriers responding to cytosolic signals have been developed for faster drug
release. The most common is a cytosolic redox signal resulting from an
elevated intracellular GSH concentration (y10 mM) compared to that in the
bloodstream (y2 mM).
115
GSH can effectively cleave the disulfide bonds to
release conjugated drugs.
66,116
It is thus used to trigger decomposition of
micelles with hydrophobic parts linked by disulfide bonds
117
or other carriers
crosslinked
118
or gated
119,120
with disulfide linkers. It has also been observed
that removal of the PEG corona could increase the drug release rate.
121,122
d
n
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3
n
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3.2.2 2S: Stealthy in Circulation and Tumor Penetration versus
Sticky to Tumor Cells
The second major material challenge is how to impart nanocarriers' stealth
ability to circulate in blood for a long time and after extravasation to penetrate
