Chemistry Reference
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OH
OH
O
H
HO
O
N
S
N
H
O
NH
Fig. 5 Man-C4-Chol.
DSPC:Chol:F-DHPE:Man-C4-Chol mixtures, Bare-liposomes (60:35:5:0),
Man-2.5-liposomes (60:32.5:5:2.5), Man-5.0-liposomes (60:30:5:5) and
Man-7.5-liposomes (60:27.5:5:7.5), were then characterized.
The mean particle size and zeta potential of liposomes ranged 90-
125 nm with a quite narrow dispersity (0.14-0.35 polydispersity index)
and
9 to 15 mV, respectively. Isolated AMs were incubated with lipo-
somes with an excess of free mannan to evaluate the uptake and in-
ternalization mechanism. The cellular association and internalization of
Man-liposomes were significantly enhanced and clearly inhibited in the
presence of competitive mannan. An in vitro confocal microscopy study
provided the evidence that the enhanced uptake of Man-liposomes in-
volved a mannose lectin-mediated mechanism in alveolar macrophages.
Besides, this uptake was found to proceed in a concentration-dependent
manner, with a considerably higher internalization process observed
with Man-7.5-liposomes and Man-5.0-liposomes than found with Man-
2.5-liposomes and Bare-liposomes. In vivo targeting of Man-liposomes to
AMs was also demonstrated after intratracheal administration to rats,
especially when Man-7.5 and Man-5.0-lisposomes were used. These Man-
based lipid formulations were selectively delivered to AMs rather than
alveolar epithelial type II cells as shown by confocal images after lung
tissue and alveolar epithelial type II cells staining with specific markers.
18
Peritoneal macrophages also constitute important targets for glycoli-
pid-based nanostructures to induce therapeutic responses against
pathogen infections such as Leishmaniasis. As a representative example,
Shimizu et al.
20
demonstrated the feasibility to induce antigen-specific
T-helper type immune response in BALB/c mice intraperitoneally im-
munized with soluble leishmanial antigen (SLA) entrapped in oligo-
mannose-coated liposomes, through an uptake of these constructs by
peritoneal macrophages. Neoglycolipids Man5-DPPE and Man3-DPPE
consisting of mannopentaose or mannotriose residues and dipalmitoyl-
phosphatidylethanolamine (Fig. 6) were synthesized and formulated
with DPPC and Chol in mole ratios around 0.08:1:1 to provide Man5-,
and Man3-liposomes. The amount of entrapped SLA was quite similar
(
25 mg/mg DPPC) whatever the liposomal formulations used.
After subsequent infection with Leishmania major, mice that had re-
ceived oligomannose-coated liposomes encasing SLA (SLA-OML) were
effectively protected against the disease, with a predominant production
of IFN-g. Man5-DPPE and Man3-DPPE-containing liposomes were pref-
erentially and rapidly incorporated into peritoneal macrophages, and the
transplantation of macrophages containing SLA-OML into the peritoneal
cavity also induced protection against L. major infection. In summary,
B
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