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OH
Cl
Cl
OH
C
16
H
33
C
16
H
33
C
16
H
33
C
16
H
33
O
N
N
O
O
HO
n
n
OH
H
OH
H
HO
n = 1, 3, 5, 7, 9
HO
H
H
OH
OH
Fig. 22 Structure of cationic glycolipids described by Mukthavaram et al.
56
the two best glycolipids of each series exploited a specific internalisation
mode. Indeed competitive inhibition with free galactose or addition of
asialofetuin almost annealed the transfection activity for both com-
pounds. Confirmation of a targeted delivery was achieved by in vivo ex-
periments on balb/c mice. A pronounced biodistribution preference to
liver was demonstrated for both cyclic and acyclic galactolipids.
3.2 Neutral glycolipids in gene delivery
As mentioned in the previous sections of this chapter, glycoside-equipped
delivery systems allow useful targeting capabilities. Indeed, they usually
lead to in vivo biodistribution in favour of specific tissues. In the case
of gene delivery, an important ecacy factor is the internalisation
step, which can be reached by non-specific interaction (electrostatic
interactions) or by specific ligand-receptor interaction (glycoside-lectin for
instance).
57
In addition, the way of internalisation influences the type of
endosome involved within the cytosol and the overall escape of plasmid
DNA.
58-60
The following examples focus on two main monosaccharides,
galactose and mannose, which are known to provide specific targeting to
hepatoma and dendritic cells respectively.
3.2.1 Neutral galactolipids. Galactoside derivatives are known to
preferentially target liver tissue and hepatoma cells in general. Therefore
for the same reasons as for drug delivery, galactolipids were used to
furnish targeting ability in the case of gene delivery. In most cases spe-
cific targeting or internalisation were confirmed by competitive inhib-
ition experiments with asialoglycoprotein or free galactose complement
in the culture media. In vivo determination of the biodistribution of the
transfection provided insights into the specific targeting potential. Two
main types of galactoside derivatives have been developed so far: (1)
monovalent galactoside; (2) multivalent systems. The latter take advan-
tage of the multipresentation known to enhance ligand/receptor inter-
action (see previous sections for references).
The structure of the galactolipid is obviously an important parameter
for an ecient transfection. The anomeric configuration has, for ex-
ample, a clear impact on the targeting specificity. Singh et al. prepared a
and b cholesteryl galactosides.
61
The b-anomer in association with cat-
ionic cytofectin and DOPE in a 1 : 4 : 4 molar ratio respectively, provided
better transfection activity of HepG2 cells. The b-cholesteryl galactoside
was further investigated in formulations based on cationic cholesteryl
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