Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 92

into the cavity (25-200 μL), irritation of the nasal mucosa, a molecular weight
cutoff around 1 kDa, and large interspecies variability. Furthermore, because
of the high viscosity of the lining mucosa, the diffusion rate of compounds
across the mucosal membrane must be greater than the mucociliary clear-
ance rate [96]. Vila et al. [97] have clearly shown the advantages of nanopar-
ticles (~200 nm) vs. microparticles (1.5 um) in crossing the nasal mucosa.
The results, illustrated using fluorescent microscopy, show that nanopar-
ticles with a stealth surface are transported across the nasal mucosa barrier.
However, no quantifiable data is provided, and the transport mechanism is
unknown, therefore limiting the assessment of efficacy. Research has been
done into direct nose to brain delivery of drugs through the olfactory nerve
and trigeminal nerves, the olfactory nerve delivering drugs to the rostral
brain areas and the trigeminal nerve to caudal brain areas. Wang et al. [98]
have been able to improve the absorption of estradiol into the cerebrospi-
nal fluid (CSF) through encapsulation in 260-nm chitosan nanoparticles, and
have shown significantly higher amounts of estradiol in the CSF through
intranasal administration over intravenous administration. This suggests
direct transport of the drug to the brain via the olfactory nerve. Another
in vivo study investigated poly(lactide)-poly(ethylene glycol) (PLA-PEG)
nanoparticles functionalized with wheat germ agglutinin (WGA), a lectin
[99]. Nanoparticles ~90 nm were loaded with the fluorescent molecule
6-coumarin. After intranasal administration, significantly higher concentra-
tions of the WGA-functionalized nanoparticle were observed in the olfactory
bulb, olfactory tract, cerebrum, and cerebellum compared to unfunctionalized
dye-loaded particles. This study suggests that direct nose to brain delivery is
possible when employing nanocarriers. However, intracellular transport via
the olfactory nerve could prove difficult because of the variability in nerve
diameter, which ranges from 100 to 700 nm [100].
The orotransmucosal route can occur through the buccal, sublingual, pala-
tal, or gingival mucosa and is attractive owing to the high rate of blood flow,
the avoidance of destruction by gastric acid, and the avoidance of first-pass
metabolism [70]. The routes of orotransmucosal delivery vary in permea-
bility, with sublingual being the most permeable, with buccal, and palatal
and gingival being the least permeable. Permeability is based on the relative
thickness of the epithelia and the amount of keratinization. Thinner epithe-
lia with less keratinization are the most permeable. Drug absorption through
the oral mucosa is a diffusion-driven process, thus buccal and sublingual
tissues are the principle focus of orotransmucosal drug delivery because of
their relatively high permeabilities. The sublingual mucosa is most often
used for drug delivery of acute disorders because of its high permeability
and high blood flow. Challenges of the orotransmucosal route include the
hydrophobic and hydrophilic barriers of the oral mucosa that must be over-
come, involuntary swallowing, which can result in drug loss, and an enzy-
matic barrier that causes rapid degradation of proteins and peptides. These
challenges could be overcome with engineered nanocarriers designed for