Biomedical Engineering Reference
In-Depth Information
glycoproteins are endogenously expressed in a number of tissues, certain
cells such as endothelial cells have been shown to upregulate carbohydrate
receptors in response to inflammation, such as selectins. The liver, particu-
larly, the hepatocytes express asialoglycoprotein receptor (ASGP-R) which
readily binds galactose that may serve as a means to ameliorate liver-specific
drug delivery. 99
5.6   BINDING AND UPTAKE
In order for the NM-mediated drug delivery to take effect, the drug-loaded NM
must be bound to the target tissue and cellular uptake is a prerequisite before the
drug can be delivered. Thus, movement toward the target tissue and ultimately,
to the target cell, is critical. The probability of binding or adhesion in a dynamic
environment, Padh, is given by the equation
Padh = f ( d x ,Q y , δ rec ,f atr )
where d = particle diameter, Q = flow rate, δ rec = density of the receptors, and
f atr = force of attraction between receptor and particle which is affected by the
particle ligand coverage and the NM conformation. 100
Conventional drug carriers lead to modification of the drug distribution pro-
file as it is delivered to the MPS such as liver, spleen, lungs, and bone marrow.
However, NMs as drug carriers can be recognized by the host immune system
when i.v. administered causing them to be cleared by phagocytes from the circu-
lation. 19 The size of the NMs, surface hydrophobicity, and surface coating func-
tionalities determine the level of blood components (e.g. opsonins) that bind to
its surface 19,20 influencing the in vivo fate of NMs. To enhance the chances of
success in drug targeting, it is important to prevent the opsonization while pro-
longing the circulation of NMs in vivo. The NMs can achieve this by precoating
with hydrophilic polymers and/or surfactants or by using NMs with biodegrad-
able hydrophilic copolymers such as PEG, polyethylene oxide, polysorbate 80
(Tween 80), and poloxamine. Studies have shown that PEG on NM surfaces
eliminates opsonization. 22,101
NMs undergo extravasation during entry into tumor tissues which occurs
by means of the EPR effect. 102,103 Thus, drugs carried by NMs for delivery
or nano-enabled drugs at the lower size range are preferable to the upper sub-
micron and micron sizes to achieve longer circulation half-lives through the
reduced macrophage mononuclear uptake ( Figure 5.7 ) and more efficient cel-
lular uptake. Research had established that majority of solid tumors exhibit a
vascular pore cutoff size between 380 and 780 nm, 104 but tumor vasculature
organization may differ depending on the tumor type, its growth rate, and
microenvironment. 104,105 Hence, in order for the nano-enabled drugs to reach
the tumor sites, the nanocarriers must be of a size much smaller than the cutoff
pore diameter. On the other hand, normal vasculature is impermeable to drug-
associated nanocarriers larger than 2-4 nm compared with free, unassociated
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