Biomedical Engineering Reference
In-Depth Information
gel electrophoresis (2-DE, 2D-PAGE) (Blunk et al.
1993
) or two-dimensional
differential in gel electrophoresis (2D-DIGE). At least a negative selection is
possible identifying surfaces which adsorb opsonins, thus minimizing animal
experiments.
Cells of the MPS are a relatively easy target, but the complexity starts when a
certain MPS population should be targeted, e.g. lung macrophages. After i.v. injec-
tion recognized particles are cleared mainly by the liver macrophages, up to 90%
of the injected does within 5 s, 2-5% by the spleen and only a few % by the lung
macrophages (Müller
1991
). Avoiding e.g. the uptake by the liver macrophages and
directing the nanocrystals to macrophage subpopulations is a first challenge. One
approach could be to use opsonins specific to macrophage subpopulations (Roubin
and Zolla-Pazner
1979
). For other cellular target sides, recognition by the MPS
cells needs to be avoided completely and simultaneously a homing device attached
to the surface to localize the particles at the target cells. After i.v. injection only
target cells are accessible which can be reached via the blood stream.
Kreuter et al. found that Tween 80 stabilized i.v. injected polymeric nanoparticles
could deliver the drug dalargin to the brain (Kreuter et al.
1997, 2003
). As mechanism
was identified that after injection apolipoprotein E in the blood bound to the particle
surface and mediated the adherence to the endothelial cells of the blood-brain
barrier (BBB) (Müller et al.
2001
). For paclitaxel-loaded polymeric nanoparticles
could be shown, that the drug was released in the endothelial cells and diffused
from here into the brain (Gelperina et al.
2002
; Kreuter
2001
). However, the basic
problem was that only a small part of the injected particle mass reached the brain
(e.g. loss to the liver) and that the drug loading of the particles was relatively low.
This resulted in low drug concentrations in the brain. It would be desirable to use a
nanocarrier with a very high loading capacity, i.e. using drug nanocrystals.
This was realized with buparvaqone nanocrystal suspensions. In vitro it could be
shown that the nanocrystals adsorbed apolipoprotein E. They were tested using a
toxoplasmosis animal model. After i.v. injection into mice, the parasites could be
completely eradicated in the brain (Schöler et al.
2001
). However, cure of the
animals was not achieved (Schöler
2001
) under the study design applied, which can
be a function of the design and/or some parasites still residing somewhere in the
body. The drug loading with the nanocrystals was much higher than with polymeric
nanoparticles, but after injection there was loss of drug by dissolution during their
travel time to the blood-brain barrier. To minimize this drug loss, the nanocrystals
should be coated with a thin polymer layer. The surface properties of the polymer
layer can be designed this way that apolipoprotein E is adsorbed preferentially, may
be in higher amounts than on Tween 80-stabilzed nanocrystals. For example, the
nanocrystals could be coated with the polymer of the polymeric nanoparticles by
Kreuter which proved efficient in targeting the endothelial cells (i.e. poly(butyl)
cyanoacrylate) (Schroeder et al.
1998
; Alyautdin et al.
1995
).
Another concept is to use a “taxi” for the nanocrystals to deliver them into the
brain. The taxi can be macrophages in the blood, which extravasate and travel e.g.
to sites of inflammation, including crossing the blood-brain barrier. This concept was
exploited by various research groups, e.g. Barrett Rabinow et al. (Dou et al.
2009
),
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