Biomedical Engineering Reference
In-Depth Information
viral components. Stability upon dilution in the blood may be challenged for
some microemulsion carriers such as liposomes or micelles.
38
Other potential
problems that all carriers face when introduced into the blood include
destabilization from high salt concentrations, adsorption of proteins, interac-
tions with lipids, opsonization, and phagocytosis from cells. When the drug
interacts with normal tissue because of the carrier's instability or is unable to
reach targeted tissue because it lacks long circulation, the targeted drug
delivery has failed. A common technique to increase circulation time is to add
extremely hydrophilic poly(ethylene glycol) (PEG) to oppose adsorption or
molecular interactions.
39,40
PEG interacts with water to make it thermo-
dynamically favorable for the PEG chains to extend and limit adsorption of
proteins.
41
However, long circulation is only relative and there can still be
some uptake by the MPS and other organs as well as recognition from
antibodies.
42
This is evident when PEG only increases the blood circulation
half-life of liposomes in blood by just hours.
43
Carrier size is another property that is often tuned to maximize EPR and
blood circulation half-life. Carrier sizes are usually sought to be large enough
to avoid renal clearance and small enough to escape out of fenestrations in the
tumor vasculature.
44,45
Only a fraction of the drug carrier's population will
reach the tumor as it is a matter of probability on whether the drug carrier will
happen to be on the right path to hit the narrow opening in the vascular
structure or if it will have to circulate through the body and risk uptake by
other means. Uptake can occur in other organs that have vascular
fenestrations, which vary in size by organ type.
46
Any particles too large to
pass through fenestrations can be engulfed by resident macrophages. Polymer
carriers will also possess a size distribution, as it is extremely difficult to avoid
polydispersity with synthesized polymers and assembled carriers. Furthermore,
many carriers can become more polydisperse during storage or while
circulating in the blood. Following extravasation into the tumor, size also
determines how different nanoparticles will penetrate into the core. Generally,
a smaller molecule can more easily extravasate and diffuse to penetrate into the
tumor; however, it can also diffuse away more quickly. On the other hand, a
larger particle will be retained more readily in the tumor environment, but has
a slower rate of extravasation and likely will not penetrate into the tumor core.
Figure 1.2 explains the concept how carrier localization is dependent more on
probability than targeting mechanisms.
The probability of any given nanoparticle reaching the tumor, extravasating,
entering a cancer cell, and ultimately causing an effect within that cell is
currently unknown. Imaging and tracking techniques have become increas-
ingly popular to study this issue, leading to the growth of theragnostics where
diagnosis is combined with therapy. Fluorescence resonance energy transfer
may be particularly useful as it will to determine whether microemulsions or
other complexes have dissociated.
47
Furthermore, Nomoto et al. have
developed a new imaging method to allow in vivo real time observation of
how PEGylation limits aggregation.
48
Tracking the dissociation or aggregation
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