Biomedical Engineering Reference
In-Depth Information
plasma component coats the surface of a pathogen or target particle and presents it
to macrophage cells via receptor mediated recognition of the bound component.
Classical plasma opsonins include complement factors, immunoglobulins, man-
nose binding lectin, fibronectin and b2-glycoprotein 1. Macrophage receptors to
these factors include CR1, Fc and mannose receptors. This process is highly species
specific. However, in some cases the binding of plasma components does not result
in RES targeting, but rather protects the particle from macrophage uptake. Although
the identity of these factors is largely unknown, several plasma components have
been suggested as potential dysopsonins, including IgA, a1-acidic glycoprotein
and albumin. As an example, polystyrene microparticles of approximately 1 mm
diameter display avid uptake into dendritic cells in culture in the absence of serum,
however uptake into dendritic cells is significantly reduced by preadsorption of
human serum albumin (Thiele et al.
2003
).
3.2
Effect of Size
In general, the plasma pharmacokinetics of nanomaterials after intravenous
administration is largely dependent on their renal clearance. Particles smaller than
approximately 20 kDa (or approximately 8 nm in diameter) generally pass through
glomerular filtration slits relatively unhindered, enabling ready removal from the
body via the urine. Particles that are too large for effective renal clearance are then
subjected to alternative clearance processes including metabolism (for biodegrad-
able particles), biliary excretion (after uptake via hepatocytes) and biodistribution
into tissues. Very large particles have the capacity to circulate in the bloodstream
for extended periods of time on account of their limited capacity for extravasation
via fenestrated capillaries or compromised vasculature. The limited extravasation
and biodistribution results in their increased presentation to macrophages.
All other physicochemical factors aside, smaller particles have a greater tendency
to avoid uptake via the RES, whereas larger particles represent better substrates. This
has been demonstrated in detail when comparing the uptake of liposomes or den-
drimers into draining lymph nodes after subcutaneous administration. For example,
increasing the size of small (<20 nm) dendrimers, results in both increased uptake
via the lymph, and increased uptake into draining lymph nodes (Kaminskas et al.
2009b
). However in the case of larger liposomes (40-400 nm), increasing size
results in slower clearance of the dose from the injection site into the lymphatic
system, but an increase in the proportion of the absorbed dose recovered in lymph
nodes (Oussoren and Storm
2001
). The complexity of examining RES uptake in this
way is that retention of nanomedicines in lymph nodes is dependent both on uptake
by macrophages as well as physical filtration, both of which have been demonstrated
to play a role in the retention of relatively biologically inert particles.
For particles that show relatively limited renal clearance and that do not contain
targeting groups intended to direct particles to particular organs, increasing particle
size results in long term accumulation in the liver and spleen. This has been
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