Biomedical Engineering Reference
In-Depth Information
dendrimer (PAMAM-a-CD), which showed activity approximately 100-fold higher
than that of dendrimer alone in NIH3T3 and RAW264.7 cells. This PAMAM
derivative was also superior to Lipofectin. The enhanced transfection activity is
considered to be resulted from the increased cellular association and the facilitated
intracellular trafficking of pDNA. It was found that both PAMAM generation and
the number a-CD conjugated per dendrimer affects transfection efficiency (Kihara
et al.
2002, 2003
). The structurally optimized dendrimer could delivery pDNA
more efficiently in spleen, liver, and kidney, compared with the unmodified
PAMAM (Kihara et al.
2003
). PAMAM-a-CD was also effective for siRNA deliv-
ery, and it showed higher sequence-specific gene silencing effects without off-target
effects that those of commercial reagents such as Lipofectamine
TM
2000, TransFast
TM
and Lipofectin
TM
(Tsutsumi et al.
2006, 2007
). Additionally, the modification of
PAMAM via mannosylation with subsequent a-CD conjugation could give rise to den-
drimer with improved transfer activity both
in vitro
and
in vivo
(Wada et al.
2005
).
Other chemical modifications, such as internal quaternization (Lee et al.
2003
),
PEGylation (Kim et al.
2004a
), peptide conjugation (Kim et al.
2007d
) and hydro-
phobic tailoring (Kono et al.
2005
), have been conducted to high efficient and less
toxic delivery vectors based on PAMAM. Other type of dendrimer vectors such as
poly(propylenimine) dendrimers (Fig.
5b
) (Zinselmeyer et al.
2004
), poly(L-lysine)
dendrimers (Fig.
5c
) (Kawano et al.
2004
), phosphorus-containing dendrimers
(Galliot et al.
1995
), carbosilane dendrimers (Krska and Seyferth
1998
) have also
been developed for gene delivery applications. Detailed information can be found
in recent review papers (Dufes et al.
2005
; Mintzer and Simanek
2009
).
3.7
Natural Polymers
Natural polymers including chitosan, dextran, alginate, collagen, and gelatin have
been broadly studied in areas varying from pharmaceutics, gene therapy, tissue
engineering, to biotechnology and bioengineering, mainly owing to their distinct
advantages like the presence of multiple reactive sites, excellent biocompatibility
and biodegradability.
3.7.1
Chitosan and Its Derivatives
Chitosan (CS), a linear, natural polysaccharide comprising b (1
→
4) linked
glucosamine and N-acetyl-D-glucosamine (Fig.
6a
), is obtained by the alkaline
deacetylation of chitin that exists in the exoskeleton of crustaceans and insects. Due
to its non-toxicity, low immunogenicity, and positive charges, CS is one of the most
intensively studied non-viral naturally derived polymeric gene vectors. CS can
effectively condense DNA and protect it from nuclease degradation. The transfec-
tion efficiency of CS-DNA polyplexes is mainly determined by the degree of
deacetylation, molecular weight of CS, pH, serum concentration, charge ratio of
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