Biomedical Engineering Reference
In-Depth Information
involves multiple receptor-ligand interactions, dual-ligand MPIOs were made for
the detection of endothelial P-selectin and VCAM-1 expression in a mouse model
of atherosclerosis (McAteer
et al.
2008). Dual-ligand MPIO binding to arterial
endothelium following
in vivo
intravenous injection was demonstrated by high
resolution
ex vivo
MRI (9.4T). Biodistribution studies showed that MPIO were
sequestered by the liver and spleen at er 24 hr, with no evidence of tissue infarction,
inl ammation or hemorrhage.
Examples of other targeting ligands used with Gd-based nanoparticles include
Sialyl Lewis
X
(sLe
X
), a tetrasaccharide carbohydrate associated with CD15 on the
surface of leukocytes that binds to E-selectin expressed on activated endothelial
cells. Sibson
et al.
(2004) successfully targeted E-selectin expression in rat brain
in vivo
using a sLe
X
mimetic moiety conjugated to Gd-DTPA (Gd-DTPA-B(sLe
X
)
A). Gd-DTPA-B(sLeX)A, administered systemically 3-4 hr following injection of
either IL-1β or TNF-α into the let striatum (to induce focal endothelial activation)
produced hyper-intense contrast ef ects on the activated brain endothelium on
spin-echo T
1
-weighted images, at a stage when no pathological changes were
apparent with conventional MRI. Gd-DTPA-sLe
X
A has also been used to detect
early endothelial activation following transient focal ischemia in a mouse model
of middle cerebral artery occlusion using
in vivo
MRI (9.4T) (Barber
et al.
2004).
To generate ligand diversity,
phage display
has been used to identify novel
peptides that bind specii cally to activated endothelium and are internalized by
cells expressing VCAM-1 (Kelly
et al.
2005, Nahrendorf
et al.
2006). h ese include
a VCAM-1 specii c, cyclic peptide sequence (CVHSPNKKC; termed VHS peptide)
(Kelly
et al.
2005) and a linear peptide, VHPKQHR, termed VCAM-1 internalizing
peptide (VINP) (Nahrendorf
et al.
2006). h e use of peptides for conjugation
to nanoparticles enables a greater number of peptide ligands to be attached per
nanoparticle, thereby increasing target ai nity. For example, Tsourkas
et al.
(2005)
reported that the number of VCAM-1 antibodies that can be conjugated to each
nanoparticle is limited by steric constraints to 1-2 antibodies per nanoparticle. By
contrast, the number of peptide ligands that could be attached to each nanoparticle
was increased to 4 using cyclic VHS peptides (Kelly
et al.
2005) and 20 using linear
VINP peptides, respectively (Nahrendorf
et al.
2006). In addition, Nahrendorf
et al.
(2006) demonstrated a 20-fold superior targeting ai nity of the VINP peptide to
cultured murine heart endothelial cells (MCEC), expressing high VCAM-1 levels,
compared to VHS peptide. Both VHS- and VINP-targeted nanoparticles detected
VCAM-1 expression in mouse atherosclerosis by
in vivo
MRI, and VINP-targeted
nanoparticles also detected a reduction in VCAM-1 expression in response to
statin treatment (Nahrendorf
et al.
2006). However, one drawback of this method
is that it requires the development of sophisticated cell-internalized probes that
cannot easily be applied to detect other ligands.
Finally, mMRI molecular imaging probes have been developed that both
visualize and treat disease. Winter
et al.
(2006) used paramagnetic perl uorocarbon
nanoparticles targeted to α
v
β
3
to assess the development of angiogenesis, but also
