Nanoparticles to Cross Biological Barriers - Biomaterials Science: An Integrated Clinical and Engineering Approach - page 90

Micro- and nanoparticle formulations to bypass barriers in pulmonary drug
delivery have been investigated. In particular, pulmonary delivery of nanocar-
riers may be employed to treat lung-specific pathologies, or can be directed
towards systemic drug delivery. Lung-specific ailments may include asthma,
cystic fibrosis, fungal infection, lung cancer, and tuberculosis [75, 84, 85]. The
diffusion of nano-sized molecules in the lungs (drugs, nanoparticles, peptides)
appears to be governed by factors such as size, surface charge [86], and hydro-
phobicity [79]. With regards to aerosol delivery, sub-1-μm particles are liable
to be exhaled because of their small size and virtually nonexistent inertial
impact, yet nanoparticles <100 nm are able to penetrate deeply in the lungs
and settle in the alveoli [82, 87, 88]. Thus <100 nm vectors deposit in the alveoli
and are able to be absorbed through the epithelial cells and enter the blood-
stream [77, 82, 88]. Moreover, nanoparticles <100 nm may avoid clearance via
macrophage phagocytosis [82] and are able to diffuse through the mucus
layer in the lungs [82]. In vivo studies conducted by Kwon et al. [89] show that
inhaled 50-nm fluorescently labeled magnetic nanoparticles were able to enter
systemic circulation and accumulate in tissues such as the liver, testis, spleen,
lung, and brain. Yacobi et al. [86] investigated the transcellular transport across
rat alveolar epithelial cell monolayers using polystyrene nanoparticles with
varying sizes (20 nm and 100 nm) and surface charges. Positively charged
nanoparticles were shown to exhibit a higher flux than negatively charged
particles, and 20-nm particles were shown to cross the cell monolayer more
rapidly than 100-nm particles. The influence of hydrophobicity on pulmonary
absorption in vivo of small, 60-700 Da, molecules was reviewed by Patton et
al. [79]. A range of molecules were deposited in vivo at the bifurcation of the
trachea via injection. This model has shown to be representative of lung, spe-
cifically alveolar, absorption as it avoids absorption in the nasopharynx and
oropharynx. Hydrophobic molecules were shown to rapidly absorb through
the lung within a matter of minutes, while hydrophilic molecules were
reported to take an average of 60 minutes to absorb 50% of the administered
dose. Furthermore, Dames et al. [90] investigated the feasibility of magneti-
cally targeting the lungs using superparamagnetic iron oxide nanoparticles
(SPIONs). Polyethylenimine-coated SPIONs with a hydrodynamic diameter of
80 nm were delivered via aerosol in vivo and preferentially directed to one
lung using a magnetic field. This type of technology may have implications as
a local targeting mechanism.
With inhaled therapies, it has been shown that particles must be <5 μm in
diameter to deposit in the deeper regions of the lungs, and the optimal size for
alveolar deposition is 1-3 μm. Larger particles deposit via impaction or sedi-
mentation in the bronchial pathways, and particles >10 μm are trapped in the
oropharynx by impaction [82, 88]. These particles will in turn be cleared by the
mucociliary escalator. Currently, the future of particle-borne systemic pulmo-
nary drug delivery seems to be up in the air. In 2007, Pfizer pulled Exubera, an
inhalable <5-μm insulin-carrying particle [91], off the market after discover-
ing an increased risk of cancer in former smokers [92]. Though these were not