Biomedical Engineering Reference
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intracellular trafficking of pDNA towards the perinuclear region via avb3 integrin
receptor mediated endocytosis, leading to increased transfection efficiency for Hela
cells. In another study, lactose-modified polymeric micelle encapsulating pDNA
targeted to hepatocytes, which possess abundant ASGP receptors that recognize
lactose moieties was developed for liver targeting (Wakebayashi et al.
2004b
). The
lactose micelle was significantly more efficient to transfect HepG2 cells (hepa-
toma) than the micelle-lacking lactose. A competitive assay using asialofetuin
(ASF), a natural ligand against ASGP receptors, inhibited uptake of the lactose-
installed micelle, suggesting that ASGP receptor-mediated endocytosis is a major
pathway for the cellular uptake of the lactosylated micelle.
3.3
Development of PIC Micelles from PEO
-
Polyesters
for Gene/siRNA Delivery
Polyesters are biodegradable and biocompatible polymers and have a history of
safe application in absorbable biomedical devices such as sutures. Compared to
PLAA, polyester tends to be more hydrophobic and micelles formed from PEO-b-
polyester are more stable upon dilution after intravenous injection. PEO-polyesters
such as PEO-b-PLGA and PEO-PCL have been extensively explored in drug
delivery. However, the lack of cationic moieties and untailorable polyester block in
their structures limits their use for gene or siRNA delivery. Although a few of
papers reported using PLGA-based particulate carriers to encapsulate antisense
oligonucleotides or plasmid DNA, the encapsulation efficiency of gene is often low
and the energy or complicated procedures are required to increase DNA encapsula-
tion which results in some denaturation of the DNA. Therefore, there is a need to
modify PEO-b-polyesters to enable them suitable for gene/siRNA delivery.
Modifications of PEO-polyesters have been made either by attaching cationic
blocks or moieties at the end of polyester block or functionalization of the polyes-
ter block with cationic moieties. These cationic moieties would provide anchoring
site for genetic cargoes. Amine-containing group was attached to the end of
PEO-PCL to prepare amine-terminated PEO-PCL (PEO-PMCL) which can
effectively encapsulate DNA by electrostatic interaction to self assemble into
micelles (Jang et al.
2006
). Compared to physically encapsulated DAN in PEO-
PCL micelles, DAN encapsulated PEO-PMCL micelles showed remarkably
increased encapsulation efficiency and transfection efficiency of DNA toward
normal human fibroblast cells without introducing obvious cytotoxicity. Triblock
copolymer of PEO, PCL and PEI was synthesized by grafting the activated PEO-
PCL onto the hyperbranched PEI (Shuai et al.
2003
) (Fig.
16a
). The resulted
polymers are completely water soluble or form micelles depending on the polymer
composition. Complexation of plasmid DNA with various copolymers can form
micelle-like particles of 200 nm in diameters with neutral surface (Fig.
16b
). With
well-controlled composition over these copolymers, pDNA complexed in PEO-
PCL-PEI with high CMC or good solubility showed enhanced DNA binding and
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