Nanoparticle Cell Penetration - Aerosols: Measurement, Dosimetry, and Health Effects - page 222

the olfactory nerve and olfactory bulbs as portals of entry to the CNS. A historical perspective and
a summary of indings from more recent translocation studies are presented in a 2005 review of
nanotoxicology (Oberdörster et al., 2005). Within the area of neuronal uptake and translocation,
the review highlights the size-dependent indings from inhalation studies with manganese oxide
particles in rats that showed a predominance for uptake in the olfactory bulb, compared to the lung.
In a study of the effect of nanoparticle size, shape, concentration, and incubation time on cellular
uptake kinetics (Chithrani et al., 2006), it is speculated that nonspeciic adsorption of serum pro-
teins mediates the uptake of the nanoparticles and that the presence of these proteins on the surface
of the nanoparticles dictates uptake half-life, rates, and amount.
The role of the surface groups and the charge they carry is paramount to the behavior of nano-
materials in vivo . Surface groups can make the material hydrophilic, hydrophobic, lipophilic, lipo-
phobic, or catalytically active or passive. In a study to evaluate the effect of neutral, anionic, and
cationic charged nanoparticles on BBB integrity and permeability using nanoparticles composed
of emulsiied wax (Lockman et al., 2004), neutral and low concentrations of anionic nanoparticles
were found to have no effect on BBB integrity, whereas, high concentrations of anionic and cationic
nanoparticles disrupted the BBB.
Nanoparticles have been used for pharmaceutical and medical applications for over 30 years
and those developed for pharmacological uses are currently made from a wide array of materi-
als such as poly(alkylcyanoacrylates); poly(methylidene malonate); polyesters such as poly (lactic
acid), poly(glycolic acid), poly(ε-caprolactone), and their copolymers; polysaccharides; and pro-
teins. The choice of nanoparticle materials is based on biodegradability, intrinsic immunogenicity,
and toxicity.
A recent review (Teixido and Giralt, 2008) of the role played by peptides in BBB interactions
highlighted that the binding of a peptide-coated nanoparticle to a given receptor can result in the
nanoparticle being transported across a barrier, often with a mechanism other than that expected of
the coating. Hydrophilic surfactants have been shown to reduce nanoparticle absorption by reticu-
loendothelial system organs that alters biodistribution of the nanoparticles. Coating of colloidal
nanoparticles with block copolymers such as poloxamers and poloxamines induces a steric repul-
sion effect, minimizing the adhesion of particles to the surface of macrophages, which in turn
results in the decrease of phagocytic uptake and in signiicantly higher levels in the blood and
organs including the brain, intestine, and kidneys among others. Surface PEGylation increases the
blood half-life of nanoparticles and polysorbate-80 improves BBB transport of nanoparticles.
In a comparable review of nanocarrier-based CNS delivery systems (Tiwari and Amiji, 2006), a
number of mechanisms proposed for the BBB transport of polymeric solid and lipid nanoparticles
were summarized. The authors state that it is possible that combination of some or all of the mecha-
nisms may act to facilitate transport. The various mechanisms proposed include the following:
1. Adhesion of nanoparticles to the inner endothelial cells of brain capillaries and the
subsequent transport by passive diffusion, possibly by a larger concentration gradient.
Nanoparticle degradation products may also act as adsorption enhancers, thus contribut-
ing to increased passive diffusion.
2. Surfactants used in coating of nanoparticles may solubilize the endothelial cell membrane
lipids, thus enhancing the transport across the BBB.
3. Surfactant-coated nanoparticles, particularly polysorbate coated, administered intrave-
nously, become further coated with absorbed plasma proteins, especially, apolipoprotein
E (Apo-E), leading to this inal product being mistaken for low-density lipoprotein (LDL)
particles by the cerebral endothelium and internalized by the LDL uptake system. Solid
lipid nanoparticles may also transport drugs across the BBB by this mechanism.
4. Components of nanoparticle structures might open the tight junctions of the brain capil-
lary endothelial cells, and allow the penetration of surfactant-coated nanoparticles into
the CNS.