Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 89

these routes of administration represent significant barriers. Instead of
spending large amounts of resources to modify a drug to improve its tis-
sue adsorption, nanocarriers can be engineered to transport any type of
drug across biological barriers, increase adsorption, and reduce drug deg-
radation in the site microenvironment [64-71]. Molecules can be transported
through an epithelial membrane by either paracellular transport or transcel-
lular transport. Paracellular transport is a one-step passive phenomenon that
occurs when molecules move between cells by crossing tight junctions [72].
Transcellular transport can be either an active or passive two-step process
and occurs when the molecule crosses both the apical and basolateral mem-
brane. In most epithelia, tight junctions have a relatively high permeability,
as this surface is involved in vectorial transport for the absorption of nutri-
ents or other necessary molecules [72].
Pulmonary delivery
Pulmonary drug delivery is an efficient route of administration for rapid
systemic delivery and quick onset of pharmacological activity. It avoids first-
pass hepatic clearance, has reduced enzymatic degradation, and presents a
high surface area for drug absorption [73, 74]. The lower respiratory tract is
composed of a large tube, the trachea, which branches into two bronchiole
tubes, and then a series of diverging conduits that decrease in size and ter-
minate in the alveoli [75, 76]. The alveoli are small sacs that provide a large
surface area, approximately 100 m 2 [74, 75, 77], for gas exchange. The cellular
makeup of the alveolar sacs consists of thin, simple squamous epithelial cells
(type I cells), larger epithelial pneumocytes (type II cells), and alveoli-spe-
cific macrophages [78]. Type II cells secrete pulmonary surfactant that aids
in reducing lung surface tension and inhibits protein degradation [79, 80].
Type II cells are also the progenitor of type I cells, which represent the most
prevalent cell type and serve as the site of gas exchange. The alveolar mac-
rophages protect the lungs by continually migrating throughout the alveoli,
engulfing microorganisms and particulate matter. A mucus layer also covers
the airway and bronchioles [81]. This layer is cited as being approximately
15 μm in the airway and 55 μm in the bronchioles. This mucus is gener-
ally biphasic with a solution-type layer and a gel layer. The solution layer is
moved upward by what is known as the mucociliary escalator, which acts to
clear particulates from the airway. Mucus in the nasal cavity is turned over
approximately every 20 minutes, whereas mucus turnover in the pulmonary
airway is thought to be more on the scale of every 4-6 hours [81]. The physio-
logical characteristics of the pulmonary system, such as high alveolar surface
area coupled with thin squamous cells, provide rapid access to a high volume
of blood. However, drug delivery via the pulmonary route must overcome
several barriers in order to be effective, including premature deposition in
the upper airways [82], entrapment by the mucus membrane and clearance
by the mucociliary escalator [81, 83], and alveolar macrophage clearance [74].