Biomedical Engineering Reference
In-Depth Information
Nanotechnology for Stem-Cell Imaging
The fields of stem cells and cell-based therapy have benefitted tremendously from
nanotechnology, which has provided many resolutions for the problems associated with
stem-cell imaging. Nanotechnology delivers a diversity of choices for straightforward
stem-cell tagging, and does not preclude the use of additional methods, including reporter-
gene approaches. Stem-cell imaging methods preferably use intracellular labeling, which
may produce contrast for one imaging modality (unimodal type) or for several modalities
(multimodal type).
Iron Oxide Nanoparticles
Iron oxide nanoparticles are characterized by a strong negative (hypointense) signal on
MRI. The excellent detectability of iron oxide was initially observed as artifacts related to
the use of mascara [9-11]. The coating of iron oxide nanoparticles with polymers facilitated
biocompatibility and protection against clumping [12]. There is an assortment of iron oxide
nanoparticles for cell tagging in various sizes, ranging from micron-sized [13] to nanometer-
sized particles [14]. Iron oxide particles are the most often used agents for stem-cell imaging.
Initially, iron oxide nanoparticles were used for
ex vivo
tagging of peripheral blood mono-
nuclear cells [15], and then this technology was successfully applied to neural stem cells (NSCs)
[16-19]. It was found that the size of iron oxide nanoparticles governs the effectiveness of their
uptake by cells, with a higher tagging efficacy by nanoparticles ~70 nm diameter (SPIO) as
compared for ultrasmall iron oxide nanoparticles (USPIO) [20]. One of the SPIO formula-
tions (Feridex
®
) has been approved by the Food and Drug Administration (FDA) for clinical
use as a contrast agent. This spurred a preclinical research on labeling efficiency with the
eventual establishment of methods for tagging of nonphagocytic cells, including stem cells,
and the eventual application of Feridex
®
for clinical stem-cell transplantations [21-23].
Unfortunately, the company ceased production of Feridex
®
in 2008 for economic reasons,
which left the field without a clinical grade formulation of SPIO. While another iron oxide
nanoparticle-based drug (Feraheme
®
) has been recently cleared by the FDA for treatment of
iron deficiency anemia its application to cell tagging is more challenging due to the USPIO.
However, the efficient tagging of cells by Feraheme
®
has been recently demonstrated [24, 25].
Further advances through nanocomplex self-assembling, by a combination of Feraheme
®
, hep-
arin, and protamine, resulted in larger, more easily internalized complexes of ~100 nm in size
[26]. It should be emphasized that all these agents were approved by the FDA for a different
application; thus, they would have to be used off-label for clinical cellular imaging.
The contrast enhancement of iron oxide nanoparticles is exceptionally strong, and has
enabled single-cell visualization [27, 28]. However, the persistence of SPIO and contrast
within the tissue despite cell death complicates the interpretation of imaging results [29-31].
Consequently, iron oxide nanoparticles are excellent for short-term monitoring of cell dis-
tribution, however, the persistent presence of SPIO in the tissue precludes its utility for the
long-term imaging of stem-cell fate.
Due to the current limitations of iron oxide nanoparticle formulations, there is continued
effort to advance their properties by surface modifications, through the application of new
coatings characterized by superior labeling and safety profiles. Poly(
N
,
N
-dimethylacrylamide)-
coated maghemite [32], aminosilane coating [33], amine surface modification [34], carboxy-
methyl chitosan modification [35], 1-hydroxyethylidene-1.1-bisphosphonic acid (HEDP) coating
[36], nontoxic protein transduction domain (PTD) conjugation [37], higher density carboxyl
groups modification [38], and D-mannose modification [39] have been used for this reason.
