Biomedical Engineering Reference
In-Depth Information
needed to produce equivalent levels of microvascular dysfunction, oxidative stress, and nitric oxide
(NO) quenching. The study also determined the changes produced on nanoparticle exposures in the
reactive species and endogenous NO production. In the study, fine TiO
2
(primary particle diameter
~1 μm) and TiO
2
nanoparticles (primary particle diameter ~21 nm) were exposed to rats via aerosol
inhalation. The results showed that nanoparticle exposure led to significant increase in the micro-
vascular oxidative stress by around 60% and nitrosative stress by around fourfold. These reactive
stresses corresponded with a decline in NO production in a dose-dependent manner. Furthermore,
radical scavenging resulted in a partially restored NO production and normal microvascular activ-
ity. These results showed that nanoparticle exposure leads to an increase in local reactive species
because of decrease in NO bioavailability and microvascular dysfunction.
In another study, Scholer et al. [80] studied the behavior of murine macrophages in the presence of
different concentrations of SLN. The SLN consisting of stearic acid or dimethyl-dioctadecyl ammo-
nium bromide were found to be cytotoxic at the concentration of 0.01%, whereas SLNs consisting
of triglycerides, cetylpalmitate, or paraffin lipids were found to be safe at the same concentration.
The authors concluded that decreased production in IL-6 was the possible reason for this type of
toxicity. In a separate study containing high doses of compritol and cetyl palmitate, it was suggested
that the toxicity is dependent on lipid matrix as well as administered doses. The results were based
on histopathology and it was found that high-dose compritol containing SLN formulation led to the
accumulation of lipids in the liver and spleen of mice and resulted in pathological alterations.
7.3.2.5 Conversion of Polymers/Lipids
Polymers and lipids have a significant tendency to convert into different polymorphic forms. These
conversions can easily take place in biological fluids where various enzymes/surfactants are pres-
ents as well as there can be significant changes in pH. The positive charges on cationic lipids present
in SLNs can promote nonspecific binding to circulating blood cells such as erythrocytes, lympho-
cytes, as well as endothelial cells. Likewise, the presence of unprotected surface negative charges
on lipid molecules such as phosphatidylglycerol and phosphatidylserine serve as binding sites for
plasma opsonin, which favors uptake by macrophages. No systemic studies have been carried out to
study these changes/conversions in polymeric and SLNs. Many studies in inorganic nanoparticles
have shown that ultrafine TiO
2
particles caused more inflammation in rat lungs than exposure to fine
TiO
2
[81,82]. Warheit et al. in their studies reasoned that the differences in toxic potencies seem to
be a result of their unique size, surface area/activity, and/or crystal properties [83-85]. Since differ-
ent polymorphic forms of polymers and lipids can result in changes in crystal properties, it can be
assumed that toxicity of polymers can be associated with these aspects of PNs and SLNs.
7.3.2.6 Degradation of Polymeric/Lipid Nanoparticles
Once distributed and sequestered in cells, the core nanoparticle metabolic processing mechanism
is still not fully addressed. Degradation of lipids during sterilization is an important issue in SLNs
as it can cause potential toxicity. Polymer-based nanoparticles and super-paramagnetic iron oxide
nanoparticles for magnetic resonance imaging contrast agents are shown to degrade, but quantum
dots (QDs), fullerenes, and silica nanoparticles are examples of nanoparticles without clear indica-
tion of degradation
in vivo
[86-88]. For example, Fischer et al. [89] and Ballou et al. [90] show
that the core ZnS-capped CdSe QDs remain intact and fluorescent
in vivo
after 1 month; however,
neither study analyzed the metabolism of the organic coating on the nanoparticles' surface. The
breakdown of the nanoparticles could elicit unique molecular responses that are not predictable
and, thus, the understanding and cataloging of what, when, and how much nanostructures degrade
are extremely important.
7.3.2.7 Route of Administration of Polymeric/Lipid Nanoparticles
PNs and SLNs can be delivered using various administration routes. In some cases, a nanoparticle
with similar composition could be delivered using different routes of administration. Since the
