Biomedical Engineering Reference
In-Depth Information
concentration of Pt in the plasma and tumor, respectively, suggesting prolonged circulation of
Pt and specifi c accumulation in the tumor. The micelles did not increase the plasma BUN at the
concentration that free CDDP induced a remarkable increase. Thus, CDDP-loaded micelles are
considered to restrain nephrotoxicity, the dose-limiting factor of CDDP, while exhibiting tumor-
specifi c accumulation [207].
DNAs are negatively surface charged and are diffi cult to be delivered into cells because of the
cell surface charge counteraction. Polycations can form ion complexes with DNA, preventing the
degradation of
in vivo
enzymes and providing the facility for penetrating the cell membrane by
changing the surface charge of the complex [208]. Thus, polycations, such as polyethylene imine
(PEI), are usually employed as nonvirus vectors for
in vivo
gene delivery [209,210]. Poly(l-amino
acid) with positive charge at the side chain, poly(l-lysine) (PLL), is also a commonly adopted
gene carrier in gene therapy. The positive charge of PLL makes it possible to form an ion complex
with the negatively charged DNA, thus preventing the gene from being degraded by the enzymes
in vivo
[211].
Block copolymer consisting of PLL and PEG forms polyion complex micelles with DNA,
resulting in nano-sized core-shell particles with PEG hydrophilic outer shells. As the same concept
described above, the PEG outer shells can keep the particles stable in blood circulation, preventing
the uptake of micelles from the RES
in vivo
. This kind of formulation is possibly a potential nonvirus
gene delivery vector [212]. Thus, the polyion complex micelles of DNA and block copolymer of PLL
and PEG having self-assembling core-shell structures were prepared. These micelles were spherical
nano-particles with small absolute values of zeta-potential. The micelles with shorter PLL lengths
showed lower stability in the blood stream. After intravenous injection of the micelles having the
charge ratios of 1:4, supercoiled DNA was observed for 30 min and open circular or linear DNA was
seen for 3 h. The micelles were found to be effi ciently transfect into HepG2 cells. This gene delivery
system is considered to be intrinsically effi cient.
The polyion complex micelles derived from different polycations and PEG were further modi-
fi ed by attaching so-called signal molecules at the surface to improve the active targeting behav-
iors. Proteins [209], lactose [213], and galactose [214] are employed as the targeting molecules. The
PEGs here not only act as the hydrophilic layer to stabilize the micelles, but also act as a spacer
for the targeting molecules that need to move freely to attach the receptor site of the tumor cell
surface.
10.4.5 “S
MART
” M
ICELLES
FOR
D
RUG
D
ELIVERY
A
PPLICATION
The so-called “smart” micelles mean those that respond to the environmental changes or to the
adscititious physical or physiological processes to regulate the behavior of the micelles themselves
and the release behaviors of the drugs from the micelles. The affected part of the body generally suf-
fers some kinds of physiological changes such as higher temperature, lower pH value, and specifi c
type of proteins compared with the normal tissues. Making use of this unconventionality, scientists
designed and developed special drug delivery systems to control the drug release processes that
specifi cally respond to certain kinds of diseases. On the other hand, adscititious processes can also
be applied to certain affected sites of the body to enhance the accumulation of drug-loaded carriers
and accelerate the release of the drugs from the carriers, thus to tone up the curative effect. Here,
some examples of the “smart” micelle drug delivery systems are introduced.
In a polymeric micelle drug delivery design, DOX was chemically conjugated to the termi-
nal end of a di-block copolymer of PLLA and PEG via two acid-cleavable linkages. DOX was
connected to the terminal group of PLLA block in the block copolymer through a hydrazone bond
and a
cis
-acotinyl bond. Micelles were prepared by self-assembly of the DOX-conjugated PLLA-
PEG block copolymers in aqueous solution. The size of the micelle was about 89.1 nm. The critical
micelle concentration (CMC) was about 1.3 mg/ml. In an acidic condition, which is typical in the
