Environmental Engineering Reference
In-Depth Information
synthesized by liver that binds to endogenous iron in plasma. Transferrin, after
interaction with its surface receptors, undergoes endocytosis into the acidic
compartment. In an acidic environment iron dissociates from transferrin, and
dissociated transferrin recycles after being released from cells. Enhanced
cellular uptake and reduced exocytosis were shown by the transferrin-
conjugated nanoparticles loaded with PTX. Nanoparticles consisted of a
shell of biodegradable polymer (PLGA). Nanoparticles showed greater anti-
cancer activity and more sustained effect compared to free drug or conjugated
nanoparticles [
57
].
(c) Physical targeting. Other targeting approaches rely on the fact that many
pathological processes present either a slight increase in temperature or
decrease in pH. Physical targeting refers to delivery systems that release a
drug only when exposed to a specific microenvironment, such as a change in
temperature or pH or the use of an external magnetic field.
The tumor extracellular pH, which is slightly lower than normal tissue pH,
is the distinguishing characteristic of most solid tumors. The tumor extracel-
lular pH ranges from pH 5.7-7.8 measured with invasive microelectrodes,
with a mean value of 7.0, but most of the pH values are below pH 7.2, with
normal blood pH remaining constant at pH 7.4. This is mainly attributed to the
higher rate of aerobic and anaerobic glycolysis compared to normal cells
[
58
]. Cellular compartments, such as endosomes and lysosomes, exhibit
even lower pH levels of approximately 5-6. pH-sensitive block copolymer
micelles capable of dissociating in response to decreased pH levels have been
designed to free their incorporated drug molecules upon accumulation at the
tumor site and/or entry into the cytoplasm. Such systems are developed by
using pH-sensitive polybase poly(
L
-histidine), using pH-sensitive linkages
(hydrazone linkage), or introducing titrable groups (methacrylic acid) into
the copolymer at the hydrophilic end while modifying PMs for pH-sensitive
targeting. Micelles with a phase transition of approximately pH 7.0 are useful
for tumor targeting, in that solid tumors have a pH of approximately 7.0, but
for subcellular targeting, micelles that are responsive to pH values ranging
from 5.0 to 6.0 (endosomal-lysosomal pH) are beneficial.
Lee and co-workers have developed such a system, in which the CMC of the
PEG-
b
-poly (
L
-histidine) copolymer was found to increase, thus reducing
thermodynamic stability as the pH of the medium was reduced [
59
]. An abrupt
increase in the CMC occurs at pH 7.2, resulting in unstable micelles that
release their content. Doxorubicin-loaded PEG-
b
-poly (
L
-histidine) micelles
showed a significant increase in the in vitro intracellular accumulation of drug,
in vivo tumor localization, and tumor growth inhibition in the A2780 ovarian
tumor model [
60
] via extracellular pH-dependent targeting of the tumor. pH
sensitivity was also obtained by linking a pH-sensitive moiety between the
drug and copolymer. A hydrazone linkage between doxorubicin and PEG-
b
-
(aspartate) copolymer had been used. Such micelles showed selective release
of doxorubicin in the endosomes where pH ranges from 5.0 to 6.0. Released
drug was found to localize in cytoplasm and eventually in the nucleus.
