Biomedical Engineering Reference
In-Depth Information
to non-parenchymal cells after IV administration in mice, depending on whether
the liposomes were conventional or PEGylated (Nag and Ghosh
1999
).
Mannose-conjugated generation 5 polypropyleneimine dendrimers also distrib-
ute preferentially and rapidly to the liver and kidneys (due to renal filtration) after
IV administration in mice, and to a lesser extent in the spleen and lungs. By con-
trast, conjugation of lactose to dendrimers increased uptake via the liver and spleen
(Agashe et al.
2007
). It is therefore clear that galactose promotes cellular targeting
towards hepatocytes, whereas mannose specifically targets liver and spleen resident
macrophages after intravenous dosing.
Using a mannose targeting approach to improve delivery towards the lungs has
been limited in success, however improved delivery of the anti-HIV drug didanos-
ine into alveolar macrophages has been observed for mannosylated gelatin nano-
particles after IV administration in rats (Jain et al.
2008
). Similarly, mannose
conjugation improved the delivery of the gelatin nanoparticles into the spleen, liver
and lymph nodes. Mannose conjugation has also been demonstrated to improve the
delivery of the anti-HIV drug zidovudine entrapped within liposomes, to draining
lymph nodes when compared to administration of the drug in non-targeted lipo-
somes by subcutaneous administration (Kaur et al.
2008
). In this respect, subcuta-
neous administration of mannose-targeted nanomedicines is expected to improve
targeting and cellular internalization in both lymph node resident macrophages and
in the lymphatic endothelium that similarly express mannose receptors that mediate
lymphocyte and cancer cell trafficking.
4
Avoiding Reticuloendothelial Targeting
4.1
Reducing Surface Anionic Charge
As demonstrated previously, reduction in the extent and strength of surface anionic
charge results in reduced particle opsonisation and subsequent uptake via the liver
and spleen. This can be achieved either by changing the surface materials (either by
incorporating less anionic lipids into colloid membranes or changing the surface
functionality on nanoparticles) or by masking surface anionic charges. Lipids such
as phosphatidylserine have a permanent anionic charge and incorporation of increas-
ing amounts of these lipids into colloidal membranes increases the magnitude of the
negative zeta potential and increases RES targeting. Alternatively, anionic groups
may be masked by the inclusion of long, uncharged polymers into the particle sur-
face. A classical example of this is the use of polyethylene glycol that coils around
the particle surface, masking surface charge and neutralizing zeta potential. Since
anionic charges are prone to recognition by plasma opsonins, a greater load of PEG
(i.e., higher MW PEG) is needed to increase plasma residence and decrease RES
targeting than for cationic particles. In theory, however, any uncharged polymer that
can coat the particle surface has the potential to mask surface charges.
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