Biomedical Engineering Reference
In-Depth Information
by reducing protein adsorption and surface opsonization. This prolongs the cir-
culation of NMs which allows for the controlled release of the drugs in the blood.
I.v. injected radiolabeled carbon nanotubes appears to be retained by the liver
or spleen but are rapidly cleared (half-life of 3 h) intact from the blood by renal
excretion.
125
Control of the pharmacokinetic profile of circulating NMs allows confinement
of injected particles to the vascular system by preventing leakage or avoiding
splenic filtration. This control is useful cancer where the tumor-associated blood
vessels are leaky and serve as a potential therapeutic target.
131
Studies revealed
the molecular signatures in endothelial cells as well as the vascular and lymphatic
beds
126,132
which can be used as easy targets for specific pathological sites for
therapeutics and diagnostics.
128,133
Useful NMs that are sued as nanocarriers must
be designed to contain the appropriate targeting ligands.
82
Long circulating nano-
carriers with controlled particle stability and aggregation having appropriately
engineered surface curvature and reactivity for strong receptor binding and sub-
sequent biochemical cascades and signaling processes are among the properties
of successful nanocarriers. It is possible that the preferred method of NM deliv-
ery is direct interstitial injection wherein the fate of interstitially injected NMs is
dependent on the size and surface characteristics of the particles.
134,135
For the
NMs to be successful, the size must be large enough (30-100 nm) to avoid leakage
into blood capillaries but not too large (>100 nm) to become susceptible to mac-
rophage-based clearance. Manipulation of the NM surface can be used to control
particle aggregation at interstitial sites, controlling drainage kinetics and lymph
node retention.
134
Hydrophilic but not hydrophobic NMs repulse each other and
interact poorly with the interstitium, thus draining rapidly into the lymphatics.
Thus, nanosize particles from 1 to 20 nm in diameter extravasate from the vascu-
lature into the interstitial spaces during transport by lymphatic vessels to lymph
nodes.
136
This phenomenon is an important aspect to consider in the design of
drug nanocarriers as the extent of nodal vascularization and blood supply varies
across tissues allowing differential leakage from the blood pool through the per-
meable endothelium in lymph nodes. Nanocarrier movement from the blood and
interstitial sites to the lymph nodes provides opportunities for diagnosis where
an enhancement of signal over background can be observed. The physicochemi-
cal properties of QDs,
137
superparamagnetic iron oxide nanocrystals, and other
similar NMs are ideal for these purposes.
Aspects of tumor-targeted NM-based drug delivery systems that must be
addressed are technical and biological concerns that influence their distribution.
Challenges to these technologies are rapid opsonization in the blood and subse-
quent clearance by the RES. This process can be minimized by saturation since
at a high enough dose of NPs, the ability of the RES to clear such particles could
be exceeded.
138,139
When RES saturation was achieved, NPs not trapped in the
liver or spleen could deliver drugs to solid tumors as shown by data obtained
with the cAu-TNF vector. Even when a majority of the vector was cleared by
RES, a fraction of the drug was delivered to the tumor.