Biomedical Engineering Reference
In-Depth Information
special enzymes in lysosomes can trigger drug release from the carriers into
lysosomes.
85
Because the harsh environment of lysosomes can easily degrade
drugs sensitive to acid or these enzymes,
86,87
the drug must quickly diffuse out
into the cytosol to avoid deactivation.
Polymer-drug conjugates, in which the drugs are conjugated to the polymer
carriers via lysosomal pH-labile linkers, are the most popular design. Hydrazone
and cis-aconityl are examples of such a linker.
88,89
Ulbrich et al. conjugated DOX
to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via this hydro-
lytically labile spacer.
90
The results showed a fast DOX release from the polymer
at intracellular pH 5, whereas at pH 7.4 the conjugates retained the drug.
Recently, they synthesized new biodegradable star conjugates consisting of
poly(amido amine) (PAMAM) dendrimer cores and HPMA grafts bearing DOX
via hydrazone bonds.
89
The in vitro cytotoxicity and in vivo antitumor activity of
all such conjugates were higher than those of classic conjugates. Another example
is Wang et al.'s dual pH-responsive polymer-drug conjugate PPC-Hyd-DOX-
DA, which could respond to the tumor extracellular pH gradients via amide
bonds and the tumor intracellular pH gradients via hydrazone bonds.
91
Lysosomal degradable peptides [e.g. glycylphenylalanylleucylglycine (GFLG)],
which are cleavable by lysosomal enzymes to release the drugs, are also used for
drug conjugation.
74,92
For instance, DOX was conjugated to HPMA copolymers
via GFLG peptides to form a cleavable HPMA-GFLG-DOX conjugate.
74
Lysosomal pH has also been used to trigger drug release from pH-sensitive
nanoparticles.
93,94
For example, pH-sensitive micelles composed of reducible
poly(b-amino ester) (RPAE) cores dissociated rapidly in an acidic environment
and at high levels of reducing reagents, inducing fast intracellular release.
94
Carriers with a core made from amine-containing hydrophobic polymers, such
as polyhistidine (PHis), can be protonated and thus dissolve in acidic lysosomes,
thereby releasing the drug.
95
Our group showed that a rapid cytoplasmic release
from carriers could increase the anticancer activity of drugs.
96,97
The additional advantage of such amine-containing polymers is that they
may also have endosomal membrane-disruption activity induced by a ''proton
sponge'' mechanism,
98
and thus disrupt the lysosomal membrane and further
release the drug into the cytosol. Some specially designed polyacids, such as
poly(propylacrylic acid) (PPAA),
99,100
were shown to disrupt endosomes at
pH 6.5 or below, causing the cytosolic release of cargo molecules.
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(2) Intra-cytosol release
An alternative to the carriers designed for intra-lysosome release discussed
above is carriers designed for intra-cytosol release (lower path in Figure 3.7). Such
intra-cytosol-release carriers retain the drug until escape from the endosome/
lysosome
101
and then release the drugs into the cytosol, hence avoiding lysosomal
drug retention and degradation. This is particularly important in small interfering
RNA (siRNA) or gene delivery and thus various approaches have been explored
to facilitate the endosomal release of DNA or RNA complexes.
102,103
In this
approach the carriers must respond to the lysosomal environment for lysosomal
escape and to the cytosolic environment for drug release.
