Biomedical Engineering Reference
In-Depth Information
for this lung specific accumulation is not clear although a similar pattern of
biodistribution has been observed with several cationic nanoparticles, where most
of the injected dose is recovered in the lungs, with accumulation in the liver being
the second most common fate of particles 10 min after initial IV administration
(Al Jamal et al.
2009
).
Anionic particles (both lipid and non-lipidic), as discussed previously, are sub-
strates for opsonins and therefore are targeted more avidly towards liver and spleen
macrophages. Furthermore, increasing the anionic strength of the particle increases
both the degree of opsonisation and the extent of liver targeting. This was demon-
strated using arylsulphonate and succinic acid capped polylysine dendrimers
(Kaminskas et al.
2007
). A generation 4 dendrimer containing 32 surface succinate
groups (weakly acidic) did not show any evidence of opsonisation and was excreted
via the urine (Fig.
7
). A small generation 3 dendrimer containing 16 surface ben-
zene sulphonate groups (stronger anion) showed some evidence of plasma opsoni-
sation and was targeted more avidly towards the liver. Increasing anionic surface
charge further by increasing the number of anionic groups to 32 benzene sulpho-
nates on a generation 4 dendrimer resulted in progressively increasing degree of
opsonisation plus increased uptake via the liver. The dendrimer with the strongest
surface anionic charge (the generation 4 benzene disulphonate dendrimer) also
showed a massive increase in uptake via the spleen such that the proportion of the
injected dose recovered in the spleen was higher than the proportion of the dose in
liver tissue (on a recovered dose per gram of tissue basis). A similar observation is
seen with lipid colloids where increasing anionic surface charge increases uptake
by the spleen more so than the liver.
3.4
Effect of Particle Hydrophobicity
The hydrophobicity of administered particles has a significant influence on the RES
targeting of the system, in particular to the liver. For example, by modifying the struc-
tural hydrophobicity of dendrimers, the extent of liver targeting of systems with simi-
lar size and surface charge can be altered significantly. An example is a comparison
between PAMAM-core dendrimers and more hydrophobic diaminobutane (DAB) -
core dendrimers labeled with Gd contrast agent. Intravenous administration of the
DAB-core dendrimer resulted in preferential accumulation of the MRI contrast agent
in the liver 15 min after dosing, whereas PAMAM dendrimers of the same size were
located in the blood vasculature and bladder/kidneys (Kobayashi et al.
2001b
)
(Fig.
8
). Similarly, subcutaneous administration of Gd-DAB dendrimers resulted in
better retention and resolution of the contrast agent in draining lymph nodes
(Kobayashi et al.
2003, 2006
). The reason for this effect may be due to increased
capacity for hydrophobic interactions of the particles with plasma proteins, resulting
in the recognition of particles as being opsonised by liver Kupffer cells. Another
mechanism may be the receptor mediated recognition of more hydrophobic particles
by macrophage receptors that recognize low density lipoproteins.
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