Antiangiogenic tumor treatment: early noninvasive monitoring with USPIO-enhanced MR imaging in mice.
OBJECTIVE
To prospectively investigate steady-state blood volume measurements for early quantitative monitoring of antiangiogenic treatment with ultrasmall superparamagnetic iron oxide (USPIO)-enhanced magnetic resonance (MR) imaging.


METHODS
The institutional animal care committee approved all experiments. HT-1080 fibrosarcoma-bearing nude mice were injected with a thrombogenic vascular targeting agent (VTA) (11 nude mice, 20 tumors) or saline (12 nude mice, 20 tumors). USPIO-enhanced (SH U 555C) MR imaging was performed after the VTA was administered. USPIO-induced changes in tissue R2* (DeltaR2*) were measured with a T2-weighted dual-echo echo-planar imaging sequence, and the vascular volume fraction (VVF) was calculated. Parametric DeltaR2* maps were analyzed with respect to tumor perfusion patterns. Correlative histologic analysis was performed for grading of tissue thrombosis, and tissue perfusion was quantified with fluorescent microbeads. Unpaired Student t test and Spearman nonparametric correlation coefficient were used for statistical analysis.


RESULTS
The DeltaR2* values were significantly (P < .001) reduced shortly after treatment initiation (mean DeltaR2*, 0.017 msec(-1) +/- 0.0014 [standard error] in control animals vs 0.005 msec(-1) +/- 0.0007 in animals that received VTA), which was also reflected by a decrease in the VVF (2.47% +/- 0.18 vs 0.41% +/- 0.48, P < .001). Histologic analysis revealed various degrees of tumor thrombosis after VTA treatment that correlated inversely with the DeltaR2* values (r = -0.83). Moreover, tumor perfusion measurements corroborated the MR results, indicating a significant reduction in tissue perfusion after VTA treatment (mean tissue fluorescence, 570.4 arbitrary units [au] per gram +/- 27 vs 161.7 au/g +/- 17; P < .05).


CONCLUSIONS
USPIO-enhanced MR imaging enables early monitoring of antiangiogenic treatment of tumors.
Persigehl
Thorsten
T
Department of Clinical Radiology, University Hospital Muenster, Albert-Schweitzer-Str 33, D-48129 Muenster, Germany.
Bieker
Ralf
R
Matuszewski
Lars
L
Wall
Alexander
A
Kessler
Torsten
T
Kooijman
Hendrik
H
Meier
Norbert
N
Ebert
Wolfgang
W
Berdel
Wolfgang E
WE
Heindel
Walter
W
Mesters
Rolf M
RM
Bremer
Christoph
C
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage*; D003911:Dextrans; D005260:Female; D052203:Ferrosoferric Oxide; D005354:Fibrosarcoma / Q000098:blood supply*; D007275:Injections, Intravenous; D007501:Iron / Q000008:administration & dosage*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D009842:Oligopeptides; D010087:Oxides / Q000008:administration & dosage*; D011446:Prospective Studies; D018709:Statistics, Nonparametric
D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D003911:Dextrans; D058185:Magnetite Nanoparticles; D009842:Oligopeptides; D010087:Oxides; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide