Biomedical Engineering Reference
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a
b
c
O
O
R
R
O
H
R
1
R
1
O
HO
OH
R
1
H
CH
3
R
2
N
N
NH
N
N
N R
1
HO
N
R
1
O
R
1
O
O
R
O
Fig. 8
The chemical structures of lipidoids
(Dass
2002
; Tseng et al.
2009
; Lv et al.
2006
). In addition, lipoplexes exhibit an
immunostimulation effect, a phenomenon that may either be harmful or beneficial.
Besides toxicity, low transfection activity, limited targetability, and non-specific
interactions with the blood components as well as with extracellular matrix are the
major limitations of vectors based on lipoplexes (Dass
2004
). Thus, efforts have
been made to develop high effective and low toxic lipids.
4.2
Lipid-Like Molecules for Gene Therapy
More recently, Anderson et al. have developed a combinatorial library of lipid-like
materials, termed lipidoids, simply through the conjugate-addition of amines to an
acrylate or acrylamide (Fig.
8a, b
) (Akinc et al.
2008
). Over 1,200 structurally
diverse lipidoids were synthesized. From this library, the authors identified lipi-
doids that facilitate high levels of specific silencing of endogenous gene transcripts
when complexed with either siRNA or single-stranded antisense 2¢-O-methyl (2¢-
OMe) oligoribonucleotides targeting microRNA (mRNA). The safety and efficacy
of lipidoids were examined in three animal models including mice, rats and nonhu-
man primates. Lipidoid-based formulations containing either siRNA or anti-miR
showed potent, specific and durable effects on gene expression
in vivo
in liver, lung
and peritoneal macrophages. The same group has also synthesized epoxide-derived
lipidoid library by efficient ring-opening reaction between epoxides and amines
(Fig.
8c
) (Love et al.
2010
). From this library, an effective formulation has been
identified that enables siRNA-directed liver gene silencing in mice at doses below
0.01 mg/kg. This formulation was also shown to specifically inhibit expression of
five hepatic genes simultaneously, after a single injection. Furthermore, the poten-
tial of this formulation was validated in nonhuman primates, where high level of
knockdown of the clinically relevant gene transthyretin was observed at doses as
low as 0.03 mg/kg. These promising results imply that these lipid-like vectors may
be developed to clinically usefully formulations for gene therapy. In addition, the
common structural features of these materials may provide certain design criteria
for creating high efficient transfection agents.
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