Abstract
The aim of this study was to evaluate the capacity of BR55, an ultrasound contrast
agent specifically targeting vascular endothelial growth factor receptor 2 (VEGFR2),
to distinguish the specific anti-VEGFR2 therapy effect of sunitinib from other anti-angiogenic
effects of a therapy (imatinib) that does not directly inhibit VEGFR2. Sunitinib,
imatinib and placebo were administered daily for 11 d (264 h) to 45 BalbC mice bearing
ectopic CT26 murine colorectal carcinomas. During the course of therapy, B-mode ultrasound,
contrast-enhanced ultrasound and VEGFR2-targeted contrast-enhanced ultrasound were
performed to assess tumor morphology, vascularization and VEGFR2 expression, respectively.
The angiogenic effects on these three aspects were characterized using tumor volume,
contrast-enhanced area and differential targeted enhancement. Necrosis, microvasculature
and expression of VEGFR2 were also determined by histology and immunostaining. B-Mode
imaging revealed that tumor growth was significantly decreased in sunitinib-treated
mice at day 11 (p < 0.05), whereas imatinib did not affect growth. Functional evaluation revealed that
the contrast-enhanced area decreased significantly (p < 0.02) and by similar amounts under both anti-angiogenic treatments by day 8 (192
h): −23% for imatinib and −21% for sunitinib. No significant decrease was observed
in the placebo group. Targeted contrast-enhanced imaging revealed lower differential
targeted enhancement, that is, lower levels of VEGFR2 expression, in sunitinib-treated
mice relative to placebo-treated mice from 24 h (p < 0.05) and relative to both placebo- and imatinib-treated mice from 48 h (p < 0.05). Histologic assessment of tumors after the final imaging indicated that necrotic
area was significantly higher for the sunitinib group (21%) than for the placebo (8%,
p < 0.001) and imatinib (11%, p < 0.05) groups. VEGFR2-targeted ultrasound was able to sensitively differentiate
the anti-VEGFR2 effect from the reduced area of tumor with functional flow produced
by both anti-angiogenic agents. BR55 molecular imaging was, thus, able both to detect
early therapeutic response to sunitinib in CT26 tumors as soon as 24 h after the beginning
of the treatment and to provide early discrimination (48 h) between tumor response
during anti-angiogenic therapy targeting VEGFR2 expression and response during anti-angiogenic
therapy not directly acting on this receptor.
Key Words
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Article info
Publication history
Published online: May 15, 2015
Accepted:
April 21,
2015
Received in revised form:
April 1,
2015
Received:
December 19,
2014
Footnotes
Conflicts of interest: The authors have indicated that they have no conflicts of interest regarding the content of this article.
Identification
Copyright
© 2015 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.
