Biomedical Engineering Reference
In-Depth Information
endosomes after the micelle uptake by the tumor cell endocytosis process, the conjugated DOX in
the hydrazone linkage was readily cleaved, releasing the intact drug from the micelles. This micelle
drug delivery system was more potent in cell cytotoxicity than free DOX [215].
Another intracellular pH-sensitive polymeric micelle drug carrier that controls the systemic,
local, and subcellular distributions of pharmacologically active drugs was reported by Bae et al.
[216]. The micelle carriers composed of the block copolymers of PEG and poly(aspartic acid). The
anticancer drug, adriamycin, was conjugated to the side carboxylic acid groups of poly(aspartic acid)
block through acid-sensitive hydrazone linkers. Under physiological conditions (pH 7.4), the hydro-
phobic interaction of DOX induces the poly(aspartic acid) block aggregates to form a core-structure
and the PEG segments the shell structure. The micelles can stably preserve drugs in this formation.
When the micelles uptake was through endocytosis of the cell, the drugs were released by sensing
the intracellular pH decrease in endosomes (pH 5-6). The experimental data clearly showed that this
system has intracellular pH-triggered drug release capability, can be enrolled into tumor cells, and
effectively fordo tumor cells with extremely low side effects.
pH-sensitive polymeric mixed micelles were prepared by mixing poly(l-histidine) (polyHis)-
PEG block copolymer and PLLA-PEG block copolymers. The micelles showed accelerated DOX
release as the pH decreased. The blending of PLLA-PEG block copolymer with polyHis-PEG block
copolymer shifted the triggering pH of the DOX to a lower value. Depending on the amount of
PLLA-PEG, the triggering pH for adriamycin release from the mixed micelles was destabilized
range of 7.2-6.6. The micelles were further conjugated with folic acid, resulting more effective
tumor cell killing due to folate receptor-mediated tumor uptake. The polyHis can promote effective
cytosolic ADR delivery into cell plasma by virtue of fusogenic activity [217].
Many other pH-sensitive micelles were designed from dendritic polymers [218], block copoly-
mer of PEG and polyacrylates [219], and block copolymers of PEG and hydrophobic poly ethers
[220], and other kinds of block copolymers have been reported. These systems aimed at forming
stable micelles in aqueous solution at physiological neutral pH but to disintegrate to release the
loaded drugs at mildly acidic pH following the break of pH-sensitive bonds that conjugate the drugs
with the carriers. In general, these formulations showed exciting results in the
in vitro
evaluation
using tumor cells or cell lines [204,221,222]. Some of these systems showed improved release con-
trol over
in vivo
examinations using animal model bearing tumor tissue. Their promise as a new
generation of advanced drug delivery carriers has attracted the interest of scientists and researchers
working on drug delivery systems and in pharmaceutical science, polymeric science, and other
related research fi elds.
Temperature-sensitive micelles are another extensively investigated series of “smart” micelle
carriers. Poly(
N
-isopropylacrylamide) (PNIPAAm) showed thermally sensitive phase transfer from
hydrophobic to hydrophilic with the increase of temperature. Copolymer of PNIPAAm and other
blocks can be synthesized through RAFT, ATRP, and other kinds of living radical copolymer-
ization. One concept of the thermo-sensitive micelles utilizes the phase transfer of PNIPAAm.
PNIPAAm acts as hydrophilic blocks at lower temperature. As the temperature rises, the PNIPAAm
is transferred into hydrophobic and the micelles shrink to release the drugs. The infected sites or
tumor tissues generally have some thermo phenomena and higher temperature than normal tissues;
when the temperature-sensitive micelles are transferred into these positions, the drugs are acceler-
ated to release, while the release might be rather lower in the normal tissue and blood circulation
where the temperature is at the normal physiological level.
Liu et al. reported thermally sensitive block copolymers of PNIPAAm-c-PDMAAm and PLGA
with different compositions and lengths of PLGA block. DOX was loaded into the copolymer
micelles by a membrane dialysis method for targeted anticancer drug delivery. The micelles are
spherical and have clear core-shell structure with size below 200 nm. The lower critical solution
temperature (LCST) of the micelles observed from the various polymers is around 39°C in phophate-
buffered solution (PBS). The DOX-loaded micelles are stable in PBS containing serum at 37°C.
When temperature rises to 39.5°C, the micelles disappear, triggering the release of DOX. At 37°C,
