Biomedical Engineering Reference
In-Depth Information
In this complicated environment, Si and SiO particulates can have clear advantages for overcom-
ing the various hurdles of oral delivery and protecting the encapsulated molecule. Si- and SiO-based
materials are hydrophilic, which increase the wettability of water-insoluble drugs in the GI tract
(Tan et al. 2010). Moreover, Si and SiO particles are low-pH resistant; this is a clear rationale for
using them as a drug-delivery system for orally administered drugs to protect them from the low
pH in the stomach.
In one
in vitro
study, the toxicity induced in human esophageal epithelial cells (NE083) was
studied with crystalline and amorphous SiO NPs. The crystalline SiO NPs showed a dose depen-
dency on Caco-2 cell viability. Compared to crystalline SiO, amorphous SiO NPs were less toxic at
doses ranging from 0.156 to 10 μg/mL. TEM analyses have shown that the morphology of esopha-
geal epithelial cells did not change following the uptake of amorphous SiO NPs. For crystalline SiO
NPs, however, it was observed that the organelle membrane ruptured and there was direct contact
between the NP and cytoplasm, which may lead to direct chemical exchanges and toxicities in
esophageal epithelial cells (Chu et al. 2011).
Consistent with the idea that toxicity is dependent on surface area, Bimbo et al. observed that
porous silicon (pSi) microparticles (10-25 μm) induced more toxicity by decreasing cell viability
than small, pSi particles (97, 126, and 164 nm) in human colon carcinoma cells (CaCo-2). Unlike
nonporous SiO particles, porous silica (pSiO) exhibit large surface areas that may cause toxicity in
cells. In nontoxic concentrations, microparticles were not internalized by the CaCo-2 monolayers
but were in close proximity to cells (Bimbo et al. 2011). At higher concentrations (2-14 mg/mL) of
mesoporous pSiO microparticles, Caco-2 cell membrane integrity weakened along with a dimin-
ished cell metabolism and increased apoptotic signalings (Heikkila et al. 2007). Smaller porous
particles (50 nm) also exhibited insignificant toxicity after treating at various concentrations from
1 to 500 μg/mL in human colon cancer cell line (HT-29) (Cheng et al. 2011). It was observed that
cell viability was particle size dependent, while the production of intracellular ROS was particle
concentration dependent.
Heikkila et al. carried out a cytotoxicity study of ordered mesoporous silica MCM-41 and SBA-
15 microparticles on Caco-2 cells. Cytotoxicity of ordered mesoporous silica MCM-41 and SBA-15
microparticles (fractions between 1 and 160 μm) was determined
in vitro
on an undifferentiated
human colon carcinoma, that is, Caco-2 cell line, taking into account the feasibility of using these
silica-based materials in oral drug formulations. For assessing the effects of the MCM-41 and SBA-
15 microparticles on Caco-2, the cellular endpoints employed were (1) cell membrane integrity,
by monitoring live-cell protease activity (AFC) and by employing the flow cytometry method; (2)
metabolic activity, by monitoring total ATP content via luminescence assay; and (3) activity of
apoptotic effectors, by caspase-3/7 activity assay. The generation of ROS, specifically, the hydrogen
peroxide (H
2
O
2
) and the superoxide radical (O
−
); was also followed. MCM-41 and SBA-15 mic-
roparticles caused cytotoxic effects on Caco-2 cells at most of the tested concentrations (0.2-14 mg/
mL) and incubation times (3 and 24 h). The effects on the cells included attenuated cell mem-
brane integrity, reduced cell metabolism, and increased apoptotic signaling. The major cause for
cytotoxicity was the heightened production of ROS, especially, the generation of the superoxide
radical (O
−
), after 3 h of incubation with the threshold dose of 1 mg/mL, evidently overwhelming
the antioxidant defenses and causing mitochondrial dysfunction, therefore increasing apoptotic sig-
naling (Heikkilä et al. 2010).
Jaganathan et al. assessed the biocompatibility of Si-based nano- and microparticles (Jaganathan
and Godin 2012). Nonporous SiONPs, pSi, and pSiO were investigated as oral drug carriers due to
their large pore volumes and, thus, the ability to load drugs in the pores. Possessing a high surface
free energy due to their large surface area, drug molecules can be absorbed into the pores to reach
a low state of free energy. The stability of pSi particles is important in the GI tract. It was shown
that bare pSi exhibited high surface oxidation after 18 h of incubation in simulated intestinal fluid
(Albrecht et al. 2009). After functionalizations with alkyl groups, Albrecht et al. demonstrated that
the porous particles had high resistance to oxidation in the gastric and intestinal fluids (Albrecht
