Biomedical Engineering Reference
In-Depth Information
27-29, 58
limited pore size of the endothelial wall in each tissue.
Since
the pore size of liver fenestrate is approximately 100 nm, NPs less
than 50 nm were recovered predominantly in the liver (~60%) and
resulted in enhanced liver uptake. And the NPs with larger dimensions
(~100-200 nm) are known to be cleared by the reticuloendothelial
system (RES), i.e., Kupfer cells in the liver.
27
In the spleen, NPs less
than 100 nm in diameter showed a minimal splenic uptake, while
almost half of the injected dose of NPs with sizes of approximately
400 nm or greater was captured by the spleen. This suggests that
the rate of splenic uptake increases as the particle size increases.
30
The reason why the liver, spleen, and bone marrow have to be
primarily considered in the PK and biodistribution study of NPs
is because these organs largely contain macrophages in their
tissues and these macrophages play a key role in clearing NPs and
macromolecules from the circulation. This system of macrophages
present in each of these tissues is known as a reticuloendothelial
system.
31
The accumulation of NPs in cells of the RES is triggered by the
specific serum proteins (opsonin) that are bound on the NPs, a process
known as opsonization. The mechanism of opsonization is not clearly
understood yet, but major opsonins have been identified. They
are fibronectin, immunoglobulins, and complement proteins.
32, 33
To minimize opsonization, the surfaces of NPs have to be modified
with a hydrophilic polymer, usually polyethylene glycol (PEG). These
PEGylated NPs can avoid protein binding by the steric hindrance
effect of the polymer chains. The surface density of the PEG chains is a
critical factor in determining the degree of reduction in opsonization.
A dense (>8 mol%) PEG layer favors the brush conformation and
effectively reduces opsonization. PEG densities less than 4 mol%
favor the mushroom conformation and do not provide protection
against opsonization.
34
Several studies with different types of NPs
have shown that the PEGylated particles have a larger AUC than that
of non-PEGylated particles or free drugs, indicating that PEGylation
leads to a reduction in RES uptake and an increased half-life.
35-40
An alternative way to reduce the RES uptake and prolong the blood
circulation of NPs may be to neutralize the surface charge of NPs.
Highly negatively charged particles have an increased rate of RES
uptake in the liver and a higher rate of clearance compared to
those of neutral particles.
Since positively charged particles tend
to form aggregates with negatively charged blood proteins such as
41
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