Chemistry Reference
In-Depth Information
Asialoglycoprotein receptor (ASGPR) and Kupffer cells receptor (KCR) are
C-type lectins. The first ones are expressed exclusively by parenchymal
hepatocytes and are very specific for galactose groups and derivatives; the
others are found on non-parenchymal cells and are less specific, binding
also to mannose and fucose. Galactose-bearing molecules are taken up by
the whole hepatic system and removed from blood circulation with rapid
internalization rates. Hence, ASGPR and KCR appear to be suitable for
liver-specific delivery.
Within this context, Managit et al. designed a new class of glycolipids,
called Gal-C4-Chol (Fig. 8) composed of a galactose head as ligand
and a lipophilic moiety (cholesterol) as a stable anchor into the liposome
bilayer.
22
After confirming the high exposure of galactose residues on
the liposomes surface by lectin-binding, in vitro uptake studies on
human hepatocellular carcinoma (HepG2 cells) and in vivo distribution
studies on mice were run to evaluate the liver targeting effect. Gal-C4-
Chol was incorporated at rates of 1.0, 2.5, 3.5, 5.0 and 7.5 mol% to DSPC/
Chol liposomes, which were tritium labeled for radioactivity monitoring.
While the first two ratios showed similar results to bare-liposomes, the
others revealed a galactose density-dependent uptake and therefore in-
ternalization (endocytosis) by parenchymal cells: the more galactose
groups, the better the ligand-receptor interaction. Due to an increase of
the surface binding, liposomes with 3.5, 5.0 and 7.5 mol% were rapidly
eliminated from blood circulation and accumulated in the liver.
Another research group focused their research on ASGPR targeting
monoglycolipids.
23
A galactose moiety was attached to a cholesterol via a
short linker (Fig. 9). A 10 mol% of this ligand (CHS-ED-LA) was integrated
into HSPC/Chol liposomes to deliver the drug model (Doxorubicin, Dox)
in the liver. The quantification of Dox by fluorescence revealed an
enhanced liver targetability and accumulation of these CHS-ED-LA in-
corporated liposomes. Furthermore, they extended their study to PEGy-
lated liposomes by introducing PEG
2000
-CHEMS, a lipid cleavable by
esterases (Fig. 9).
24
The PEGylated liposomes not only showed the same
drug targeting eciency, but they also prevented a rapid high liver con-
centration of drug. ASGPR remained unsaturated, allowing a sustained
uptake of the drug and lower damage to the liver.
In 2007, galactosylated liposomes for stavudine delivery composed of
EggPC/Chol/Gal-DMPE were studied for targeting hepatocytes in AIDS
treatment.
25
As HIV is located in macrophages amongst others, the entire
hepatic system for glycoprotein recognition was exploited, not only tar-
geting ASGPR but also KCR. In vitro and in vivo experiments to study drug
OH
OH
O
H
N
NH
O
S
H
O
HO
OH
Fig. 8 Gal-C4-Chol.
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