Chemistry Reference
In-Depth Information
2.4 Activated endothelial cell and platelet glycotargeting
Selectins are C-type lectins that were also targeted by glycolipid-based
nanosystems in the past few years. Selectins are carbohydrate-binding
molecules that bind to fucosylated and sialylated glycoprotein ligands
(sLe
x
, sLe
a
and SO
3
Le
a
), and are found on endothelial cells, leukocytes
and platelets. They are involved in tracking cells of the innate immune
system, T lymphocytes and platelets.
27
Three selectins have been iden-
tified, including E-, P-, and L-selectins. P- and E-selectins are expressed
on activated endothelial cells and platelets; L-selectin is expressed on
activated leukocytes. The specific interactions between selectins and
their ligands regulate the adhesion of leukocytes to endothelium, the first
step of inflammation. Within this context, current therapeutic strategies
are based on the principle of carbohydrate-selectins interactions either to
interrupt the adhesion of leukocytes to the endothelium and thus to
inhibit the inflammatory process or to selectively target the endothelium.
Glycoliposomes obtained from synthetic non-PEGylated (SuLe
a
-DSGA)
and PEGylated (SuLe
a
-PEG
2000
-DSPE) lipid conjugates of 3
0
-sulfo-Lewis a
(SO
3
Le
a
) (Fig. 11) were prepared to induce specific and optimal binding of
these SuLe
a
-liposomes to the receptor of P-selectin expressed on activated
platelets.
28,29
The flexible and biocompatible PEG spacer with a Mw of
2000 was incorporated between the carbohydrate domain and the lipid
backbone in order to (1) mimic the extended structure of the natural
ligand glycoprotein, (2) increase the circulation time of vesicles in vivo,
and (3) permit more exposure of the carbohydrate recognizing domain
(CDR) for effective interaction with receptors. PEG
2000
-DSPE, SuLe
a
-DSGA
or SuLe
a
-PEG
2000
-DSPE (5 mol%) were used with DSPC (55 mol%) and
Chol (40 mol%) to prepare liposomes and glycoliposomes using a freeze-
thraw and extrusion method through 100 nm membranes. The mean
vesicle size for SuLe
a
-PEG
2000
-liposomes was 113.3 nm after extrusion,
HO
OH
OH
OH
O
O
O
O
O
O
OH
HO
O
O
O
H
O
NHAc
O
OH
O
3
SO
O
SuLe
a
-DSGA
O
O
O
O
O
O
O
O
H
P
PEG
2000
-DSPE
45
OH
O
O
O
HO
OH
O
OH
OH
O
O
O
O
O
O
OH
O
O
O
O
HO
O
H
O
H
P
NHAc
45
OH
O
OH
O
3
SO
O
O
SuLe
a
-PEG
2000
-DSPE
Fig. 11 Sialylated non-PEGylated (SuLe
a
-DSGA) and PEGylated (SuLe
a
-PEG
2000
-DSPE)
lipids and PEG
2000
-DSPE.
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