Biomedical Engineering Reference
In-Depth Information
micelles with a mean size of approximately 25 nm and narrow size distribution showed two- to
threefold higher cytotoxicity than that of free PTX. In addition, increased uptake of the PTX-loaded
micelles in the plasma, ovary and uterus, lung, and kidney were observed, whereas the uptake in the
liver and brain decreased. These results indicate the high promise that Pluronic micelles can effec-
tively solubilize PTX, prolong blood circulation time, and modify the distribution of PTX [175].
The broad specifi city for other drugs of block copolymer micelles might be a valuable property for
developing new drug delivery systems to increase drug accumulation in cancer organs by encapsu-
lating the drug in micelles to prevent unwanted interactions with healthy cells.
Recently, the enhanced uptake of anticancer drugs into the tumor cell induced by ultrasound was
reported [177,178]. Pruitt and coworkers reported a stable Pluronic micelles by core-cross-linking.
The micelles were able to sequester the DOX and protect cells from the drug at low concentrations
for approximately 12 h. Application of low-frequency ultrasound resulted in a synergistic killing
effect with DOX and low concentrations of stabilized Pluronic due to release of DOX and permea-
bilization of the cell membrane [179]. One animal experiment that applied the drug-encapsulated
Pluronic micelles in ovarian cancer-bearing mice indicated that ultrasonic irradiation locally to the
tumor signifi cantly enhanced accumulation of Pluronic micelles in the tumor cells. The degree of
targeting was enhanced by a local tumor sonication [180].
This enhancement is considered to possibly have two independent mechanisms that work in
concert. The fi rst one is related to the acoustically triggered drug release from micelles that results in
higher concentration of the free drug in the incubation medium. The second mechanism is based on
the perturbation of cell membranes that results in the increased uptake of the micellar-encapsulated
drug. Under the radiation of ultrasound, the micellar-encapsulated drug tends to release from the
micelle due to micelle perturbation; meanwhile, the ultrasound induces a series of cellular changes
that enhance the accessibility of various cellular structures to drug, making it easier for the drugs
to achieve intracellular distribution. An important advantage offered by ultrasound is that the same
degree of the intracellular drug uptake may be achieved at a substantially lower drug concentration
in the incubation medium [181,182].
During the treatment of tumor with antitumor agents, the human multidrug transporter MDR1
p-glycoprotein and the multidrug resistance proteins MRP1 and MRP2 transport a range of cyto-
toxic drugs, thus often resulting in multidrug resistance in tumor cells [183]. Incorporating Pluronic
block copolymer in the cancer therapy, the micelles can sensitize multidrug-resistant (MDR) cancer
cells, increasing the cytotoxic activity of antitumor agents. This effect is attributed to the inhibition
of the most clinically relevant p-glycoprotein through the combined ATP depletion and inhibition of
p-glycoprotein ATPase activity [184]. DOX is often observed to induce the MDR of tumor organs.
In the study employing DOX/Pluronic formulation, the treatment of the cells with DOX/Pluronic
formulation signifi cantly enhanced the proapoptotic activity of the drug and prevented the activa-
tion of the antiapoptotic cellular defense, thus inducing apoptosis in the resistant cancer cells more
effi ciently than free Dox [185]. The high-frequency ultrasound showed positive effects on DOX
uptake by MDR cells from DOX/Pluronic micelles. It was observed that even a short exposure to
high-frequency ultrasound signifi cantly enhanced the intracellular DOX uptake [186].
Pluronic triblock copolymers were used to enhance the cytotoxicity of carboplatin, a metallic
anticancer agent, to rat tumor cell. Compared with control groups receiving carboplatin alone,
the great enhancement of carboplatin cell cytotoxicity with induced Pluronic were observed. The
experimental data demonstrate that Pluronic P85 is a optimal agent for increased cytotoxicity of
carboplatin in the DHB/K12/TRb rat colorectal carcinoma cell line. This study implies that the
Pluronic may act as a potential drug delivery scheme for carboplatin in cancer therapy [176].
10.4.3 A
MPHIPHILIC
B
LOCK
C
OPOLYMERS
B
ASED
ON
A
LIPHATIC
P
OLYESTERS
Aliphatic polyesters are biodegradable hydrophobic polymers. PEO-polyester block copolymers are
thus composed of hydrophilic PEO segment and hydrophobic polyester segment. The PEO-polyester
