Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 91

nano-scale formulations, the findings have put a damper on the pulmonary
delivery of insulin, and consequently on the investigation of particle-borne
pulmonary delivery. Research will therefore need to show that nanoparti-
cle-mediated pulmonary drug delivery is more effective than conventional
treatment, and is safe across a wide patient demographic. That being said, the
pulmonary route is an efficient desirable candidate for nanocarrier-mediated
drug delivery because it offers rapid absorption and extensive bioavailablility.
Transmucosal delivery
The transmucosal administration route is efficient owing to the inherent
absorptive properties of mucosal surfaces and the rich blood supply that
translates to rapid transport into systemic circulation [70]. Mucus, an adhe-
sive gel composed of a densely woven network of natural mucin polymers
interspersed with a variety of glycoproteins, creates an effective barrier to
diffusion across mucosal surfaces [81]. Furthermore, mucus is constantly
secreted and turned over, an action that serves to clear particulate matter.
Delivery across the mucosal layers will require nanocarriers to traverse this
thick web and evade adhesion to the sticky mucin fibers. The thickness of
mucus layers is known to vary between different types of tissues [81]. In
addition to the physical variability of mucosal membranes, the pH can vary
greatly depending on the physiological locations of the mucosal surface.
Studies have demonstrated that lung and nasal pH are generally neutral,
while a cross-sectional pH gradient exists in gastric mucus. This gastric pH
can change from ~1-2 at the luminal surface to a pH ~7 at the epithelial sur-
face [81]. These variations between mucosal membranes must be considered
when designing a nanoparticle for transmucosal delivery.
Two specific transmucosal routes of interest are the nasal and oral routes.
The nasal route has three possible modes of entry: the nasal epithelium [93],
the bronchial epithelium [94], and possibly a direct link to the brain via the
olfactory nerve. The oral route has two possible modes of entry: through
the oral mucosa, such as buccal, gingival, sublingual, or palatal routes [70],
and through the gastrointestinal epithelia. Drug delivery via transmucosal
routes occurs via three primary modes: paracellular uptake, endocytosis by
enterocytes, and endocytosis by membranous microfold cells (M cells) [95].
Since cells lining mucosal membranes are arranged in monolayers, particles
can translocate between tight junctions of neighboring cells, thereby induc-
ing paracellular translocation.
The nasal epithelium has moderate permeability, low enzymatic activity,
and the ability to avoid first-pass metabolism, and it displays rapid onset
of pharmacological activity, making it an attractive route for drug delivery.
Moreover, the ease of intranasal delivery may improve patient compliance
owing to the possibility of self-administration. However, drugs delivered via
the intranasal route must avoid many obstacles as well. Primary concerns of
intranasal delivery include a limited volume of drug that can be delivered