Chemistry Reference
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endocytic receptors, and proteoglycans. The lectin activity of these re-
ceptors is mediated by conserved carbohydrate-recognition domains
(CRDs). Some of these proteins are secreted and others are transmem-
brane proteins. Although they share structural homology, C-type lectins
usually differ significantly in the types of glycans that they recognize with
high anity. These proteins function as adhesion and signaling recep-
tors in many immune functions such as inflammation and immunity to
tumor and virally infected cell.
If the binding between individual lectin-type proteins and carbohydrates
is typically quite weak, strong and specific responses are often obtained
through multiple interactions between one protein and numerous carbo-
hydrates, a phenomenon known as multivalency. Hence, the binding af-
finity is strongly influenced by the branching pattern of the carbohydrate
chains, as well as the number of such branches. The enhancement of
protein-carbohydrate interactions by multivalency is termed 'glycoside
cluster effect'. In a well-known seminal study, Lee et al.
3
clearly highlighted
the importance of such an effect by evaluating the anity of the hepatic
asialoglycoprotein lectin for a range of synthetic mono-, di-, and tri-
antennary b-
D
-galactose-terminated oligosaccharides with a spectacular
anity enhancement in the ratio of approximately 1 : 1,000 : 1,000,000.
Glycolipids are particularly suited to multivalent interactions due to
their mobility and their ability to interact laterally within the membrane
plane, both as hydrogen bond donors and as acceptors. In addition to
their role in recognition phenomena, glycolipids may also affect the
physical properties of lipid membranes. Noteworthy, glycosylated lipids
are thought to influence the formation of microdomains and lipid rafts.
4
Furthermore, the high proportions of glycolipids present in some extre-
mophilic Archaea were shown to strongly stabilize the membrane struc-
ture by interglycosyl headgroup hydrogen bondings.
5,6
The finding that glycolipids may exert a positive impact on cell mem-
branes in terms of physical and cell-surface recognition properties led to
the idea that they could be advantageously incorporated into nanosys-
tems for drug and gene delivery applications. Typically, glycolipids were
introduced into lipid bilayers to provide nano-assemblies termed glyco-
liposomes and glycovesicles (Fig. 1).
7,8
In particular, nanosystems con-
taining natural or synthetic glycolipids were investigated for targeting
drugs and genes to specific disease cells via carbohydrate-lectin inter-
actions. The presence of targeting carbohydrate ligands could further
enhance cellular uptake and retention of drugs via receptor-mediated
endocytosis, which is particularly essential for the delivery of substances
that require intracellular delivery for bioactivity. It has been also shown
that strong adjuvant activities could be exhibited by the incorporation of
synthetic glycolipids into vaccine liposomal formulations. Interestingly,
subtle variations in the carbohydrate head group were found to alter the
type and potency of immune responses.
9
Liposome surface glyco-functionalizations were generally performed
via direct formulations of controlled ratios of lipids and synthetic or
naturally-derived glycolipids or chemical conjugation reactions of sugar
ligands onto the surface of preformed liposomes carrying terminal
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