Biomedical Engineering Reference
In-Depth Information
amphiphilic block copolymers are generally prepared by polymerization of cyclic lactones or lac-
tide initiated from the end hydroxyl group of PEO. They self-assemble into micelles in aqueous
solution. The formation of micelle inner core is due to the hydrophobic interaction of the biodegrad-
able polyester chains. Hydrophobic drugs are physically entrapped in the hydrophobic core through
nonpolar interaction, stabilized by the highly hydrophilic and low-toxic PEO palisade. The micelles
collapse after the degradable core-segment, and the left PEO segment fi nally permeated through
kidney and was eliminated from the body. Therefore, the PEO segments employed in PEO-polyester
micelles are generally low-molecular weight products with
M
n
less than 10,000. The typical polyes-
ter segment composed of poly (ε-caprolactone) (PCL) and poly (d,l-lactide) (PDLLA).
The micelles composed of PEO-polyester block copolymers were found to be internalized into
cells within a short culture period (several hours). The internalization process was found to be time-,
temperature-, pH-, and energy-dependent, fulfi lling the basic criteria for endocytotic uptake. In addi-
tion, there are other results that provide the evidence to support the endocytosis of the micelles by
cells. Thus, nowadays, it is widely ratifi ed that the mode of cellular internalization of PEO-polyester
micelles is endocytotic [187-189].
Hydrophobic anticancer drugs and other compounds are encapsulated into the PEO-polyester
micelles for delivery into the tumor cells and organs [190]. The copolymer derived from PDLLA
of
M
w
1866 and PEG of
M
w
3300-4000 can obtained through the drug-loading micelles with the
maximum drug-loading ability if 12 mg/g. The drug release from these micelles was reported as
mainly “degradation controlled” [191]. A PCL-PEO copolymer micelle was reported to be capable
of encapsulating DOX in the hydrophobic cores in aqueous solutions. The micelle diameter is
adjustable, increasing with the increase of PCL block length in the copolymer composition. Com-
pared with free DOX, the DOX-loaded micelles can provide hemolysis in the blood. Different
from free DOX, these DOX-loaded micelles accumulate mostly in cytoplasm instead of cell nuclei
[192]. Amphiphilic diblock copolymers based on methoxy PEG (MPEG) and poly(δ-valerolactone)
(PVL) (MPEG-PVL) that can load PTX was reported. At a certain composition, micelles of 31 nm
in diameter with a narrow size distribution can be formed, which improve the apparent aqueous
solubility of PTX by more than 9000-fold, and show excellent biological activity in human MCF-7
breast and A2780 ovarian cancer cells [193].
In addition to PEG, other hydrophilic polymers are used as shell component of polymeric
micelles. Polymeric micelles based on amphiphilic block copolymers of poly(2-ethyl-2-oxazoline)
(PEtOz) and PCL were reported as a nanocarrier for the delivery of PTX using dialysis method.
Their loading content was in the range of 0.5-7.6 wt.%, varying mainly with the block composi-
tion of block copolymers. The hydrodynamic diameters of PTX-loaded micelles were in the range
18.3-23.4 nm with narrow size distribution. PTX-entrapped polymeric micelles exhibited compara-
ble activity to that observed with Cremophore EL-based PTX formulations in inhibiting the growth
of KB cells [194].
The stability of the drug-loaded micelles is modifi ed by crosslink ing of either the core-segment
or the shell segment. Double bonds were introduced into the PCL blocks, and cross-linkable PEG-
PCL di- and triblock copolymers were synthesized. The nanoscale micelles containing hydropho-
bic PTX in their hydrophobic cores were cross-linked by radical polymerization to enhance their
thermodynamic stability. It was reported that the PTX loading did not obviously affect the micelle
size or size distribution, and the drug-loading effi ciency of micelles was enhanced signifi cantly
upon micelle core-cross-linking. The cross-linked micelles exhibited a signifi cantly enhanced ther-
modynamic stability against dilution with aqueous solvents [195]. Xu et al. reported a new type of
highly stable core-surface-cross-linked polymer micelles made from amphiphilic brush copolymers
with PCL cores and PEG or poly[2-(
N
,
N
-dimethylamino)ethyl methacrylate] (PDMA) shell. An
anticancer agent, cisplatin, could be loaded in the micelle with high-loading effi ciency (approxi-
mately 90%). This drug-loading micelle could be easily taken up by SKOV-3 ovarian cancer
cells. It was found that cisplatin encapsulated in the micelle had much enhanced cytotoxicity to
the cancer cells compared with free cisplatin. It seems that the positive charges on the micelle
