Biomedical Engineering Reference
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were assessed
in vivo.
The T
2
* - weighted images clearly identifi ed the heteroge-
neous arrangement of vessels with
3
integrins expressed on endothelial cells
(Figure 6.1). The uptake of RGD-USPIO by HUVECs was signifi cantly increased
when compared with unlabeled USPIOs, and could be competitively inhibited by
the addition of unbound RGD. The RGD-USPIO noninvasively distinguish tumors
with higher (HaCaT-ras-A-5RT3) and lower (A431) area fractions of
α
v
β
3
integrins
in HaCaT-ras-A-5RT3 tumors. A visual inspection of the T
2
- and T
2
*
- weighted
images of HaCaT-ras-A-5RT3 and A431 tumors elucidated differences in the dis-
tribution pattern of RGD- USPIO. In HaCaT - ras - A - 5RT3 tumors, a branched
network of strong signal intensity (SI) decrease was found at the border and in
certain central parts of the tumor, which was consistent with the heterogeneous
pattern of angiogenesis described in these tumors [93]. In contrast, SI changes in
A431 tumors were less pronounced and more homogeneous, with only a few spots
with a strong SI decrease being observed at the tumor periphery (Figure 6.1a).
Both, in HaCaT-ras-A-5RT3 and in A431 tumors, the T
2
relaxation times were
decreased signifi cantly more (
P
α
v
β
0.05) after the injection of RGD-USPIO than
after the injection of plain particles (Figure 6.1b). In addition, the decrease in T
2
relaxation time in HaCaT- ras - A - 5RT3 tumors (28
<
±
41 ms) was more pronounced
than in A431 tumors (14
8 ms).
On fl uorescence images, HaCaT-ras-A-5RT3 tumors showed a highly heteroge-
neous vascularization with not only large, intensively branched vascular networks
but also low-vascularized areas with only
a
few small vessels. As described else-
where [94], both discontinuous and heterogeneous
±
3
integrin expression was
found on endothelial cells and in perivascular stromal cells. In contrast, A431
tumors showed a homogeneous vascularization with predominantly small vessels
of
α
v
β
m diameter. These differences in vascular phenotypes with focal intense
vascularized areas showing high levels of
<
20
μ
3
integrins in HaCaT - ras - A5RT3
tumors, and with the more homogeneous vascularization in A431 tumors, provide
a plausible explanation of the different SI change pattern seen on the T
2
*
- weighted
MR images. In summary, RGD- coupled, APTMS - coated USPIOs effi ciently tar-
geted
α
v
β
3
integrin expressions and provided an angiogenesis imaging profi le [73] .
Sun
et al.
demonstrated an MRI nanoprobe that targets gliomas, expressing
membrane- bound matrix metalloproteinase - 2 ( MMP - 2 ) with high - level specifi city,
both
in vitro
and
in vivo
[95]. The nanoprobe is composed of an iron oxide core
coated with PEG and conjugated with the targeting agent, chlorotoxin (CTX), a
36-amino acid peptide, and demonstrated a high selectivity and binding affi nity
towards gliomas as well as towards other tumors of neuroectodermal origin [96,
97]. Reports have been made which show that CTX specifi cally binds to glioma,
medulloblastoma, prostate cancer, sarcoma, and intestinal cancer [98]. Further-
more, an
131
I-linked version of CTX is currently undergoing Phase II clinical trials
for the targeted radiation of tumor cells [99]. Previously, the same research group
tested the glioma-targeting ability of the CTX-conjugated nanoparticles [100], but
the current improved version of CTX-conjugated nanoprobes has an ability to
target gliomas specifi cally. The tumor specifi city of the nanoprobe was evaluated
in vitro
using a 9L gliosarcoma cell line through cellular uptake assays, and also
α
v
β
