Biomedical Engineering Reference
In-Depth Information
phagocytic cells such as macrophages and dendritic cells
[133,134]
. However, cel-
lular internalization of PLGA nanoparticles was also observed through fluid-phase
pinocytosis and clathrin-coated pits in vascular smooth muscle cells
[135]
.
Following uptake, nanoparticles were shown to be transported to primary endo-
somes, followed by secondary endosomes, which then fuse with lysosomes. Either
the entire particle or the encapsulated DNA must escape from these vesicles to allow
for gene expression. PLGA becomes protonated in the acidic environment of the lys-
osome. Protonation causes localized destabilization of the membrane and subsequent
expulsion of the particle into the cytoplasm
[136-138]
.
It was observed that smaller size (100 nm) of NPs showed a 27-fold higher gene
transfection than the larger size (100 nm) NPs because of the difference in cellular
uptake or the release of DNA from the NPs. Thus, the smaller size with a uniform par-
ticle size distribution is expected to increase the gene transfection efficiency of NPs
[139]
. DNA-loaded PLGA nanoparticles are evaluated for gene expression using dif-
ferent routes of administration. PLGA particles coated with pDNA administered intra-
muscularly demonstrated higher gene expression at the site of injection than naked
DNA, for a period of 2 weeks
[140]
. Oral administration of PLGA-encapsulated DNA
was also effective. Following oral administration, intestinal targeting and gene expres-
sion in the small and large intestines of mice were observed for up to 7 days after the
last administration
[141]
. Intranasal delivery of DNA-coated particles resulted in pro-
tein expression in cells from the lymph nodes and spleens of mice, detected as early
as day 1 and continued for at least 7 days
[140]
.
Parenteral administration of DNA-coated PLG microparticles
[142,143]
encap-
sulated DNA creates efficient immunization by stimulating systemic B- and T-cell
responses
[144,145]
. This confirms the role of DNA-coated or encapsulated PLGA
nanoparticles for effective vaccination. Following intramuscular (IM) or intra-
peritonial (IP) administration of PLGA particles comprised of 2 g of encapsulated
DNA encoding, individual T-cell epitopes generate cytotoxic T-cells specific for the
encoded epitopes, which are equal to those generated by 200 g of naked DNA
[146]
.
The majority of encapsulated DNA from PLGA particles was not biologically avail-
able right away, but rather becomes available over time as it is released from particles.
Thus, sustained gene expression could be achieved for a prolonged period of time
[147]
. DNA-encapsulated PLGA nanoparticles demonstrated sustained marker gene
expression
in vitro
as well as
in vivo
. The nanoparticles exhibit extended gene trans-
fection
in vivo
for period of 4 weeks
[148]
. The role of sustained and regulated gene
expression is crucial in treating certain localized disease conditions such as cardiac
and limb ischemia. PLGA nanoparticles comprised of plasmid-encoding proangio-
genic growth factors were found effective in inducing neovascularization of damaged
tissue
[149]
. Unregulated overexpression of growth factors for angiogenesis therapy
may worsen the disease by tumor formation rather than treat angiogenesis
[150]
.
4.2.2.3 Poly(Alkylcynoacrylate)
Polyalkylcyanoacrylate (PACA) NPs were first prepared by Couvreur et al
.
in 1979
(
Fig. 4.7
)
[151]
. The main characteristics of PACA particles are their abilities to
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