Nanoparticle Cell Penetration - Aerosols: Measurement, Dosimetry, and Health Effects - page 223

5. Excipients used in the manufacture of nanoparticles (e.g., polysorbate 80) may inhibit the
drug eflux system and improve the drug absorption across brain capillary endothelial cells.
6. Nanoparticles might be endocytosed or transcytosed through the brain capillary endothe-
lial cells.
The chemical identity of the surface of a nanoparticle is key to many of these possible mechanisms
and is the basis of many pharmacological approaches using the activation of natural transport routes
to penetrate the BBB.
9.6 CONCLUSION
One of the major concerns regarding the possible toxic effects of nanoparticles is the capacity
of these materials to penetrate cells and potentially translocate to other cells, tissues, and organs
remote from the portal of entry to the body. This is considered to be a necessary step in the move-
ment of particles deposited in the lung, entering the blood, acting upon cells in other tissues, and
manifesting ultimately in a physiological response.
The ability to enter the interstitium from the airspaces seems to be a fundamental property of
nanoparticles. However, the exact role that interstitialization has in human toxicity is not yet well
understood. The blood and the cardiovascular system are signiicant potential targets for adverse
effects of engineered nanoparticles. CDNP appear to be able to enhance atherosclerosis, and the
possibility that this could be a general property of nanoparticles is being examined. Size and chemi-
cal structure are likely to be important and might act through the effect that they have on lung
inlammation and oxidative stress. In the case of translocation to the blood and direct interaction
with plaques, size is likely to be important.
The unique biokinetic behavior exhibited by nanoparticles, including cellular endocytosis, trans-
cytosis, and neuronal and circulatory translocation and distribution, makes them desirable for thera-
peutic and diagnostic medical applications, but may also convey potential toxicity. The routes of
entry of nanoparticles to the CNS are becoming increasingly recognized, although the inluence of
physicochemical properties on the mechanisms remains to be fully elucidated. There is evidence
of uptake in the CNS both of particles translocating from the lungs and via the olfactory bulb. It is
expected that transport of nanoparticles across the BBB is possible by either passive diffusion or
by carrier-mediated endocytosis (Hoet et al., 2004). Moreover, as the BBB is defective in a num-
ber of locations (e.g., pineal gland, pituitary gland, area postrema, choroid plexus), nanoparticle
entry in these areas may be possible. Surface-modiied particles can interact with the receptors,
leading to uptake by endothelial cells. Also, other processes such as tight junction modulation or
P-glycoprotein (Pgp) inhibition also may play a role (Kreuter, 2001).
Understanding the role of nanoparticle structural features, effects of modiications to the struc-
ture and the ability to produce inlammation is key to elucidating the factors that render a particle
able to enter the interstitium.
Investigation of the mechanism(s) of nanoparticle translocation is an active research area.
Further detail and discussion of the aspects highlighted in this chapter and newly emerging indings
are available in the peer-reviewed literature, including publications on the biokinetics of inhaled
particles (Geiser and Kreyling, 2010), macrophage clearance of inhaled micro- and nanoparticles
(Geiser, 2010), and translocation of multiwall CNTs (Reddy et al., 2010), quantum dots (Geys et al.,
2009), and polystyrene nanoparticles (Yacobi et al., 2010), to suggest but a few.
ACKNOWLEDGMENT
The contribution is acknowledged of coauthors (Vicki Stone, Ken Donaldson, Lang Tran, Bryony
Ross, and Qasim Chaudhry) of the report entitled “Cell Penetration: A study to identify the physi-
cochemical factors controlling the capacity of nanoparticles to penetrate cells” upon which this
chapter has drawn.