We tested the hypothesis that macromolecular agents will have a greater sensitivity in identifying areas of high regional mammary tumor permeability-surface area products than low molecular weight agents. New modalities such as ultrasound, MRI, and nuclear medicine may improve breast cancer diagnosis(1). MRI can detect small tumors, 1 mm, with nearly 100% sensitivity(2) and can differentiate benign from malignant tumors with an accuracy of only 30 to 40%(3). A need exists for more accurately characterizing tumor specificity with MR mammography. Dynamic contrast enhanced MR mammography shows promise, and is based on differences in capillary density. Only a subset of tumor cells acquire angiogenic activity and this results in heterogeneous capillary density and surface area(4). High regional capillary density indicates poor prognosis(5). Tumor secreted factors induce angiogenesis, including vascular endothelial growth factor (VEGF), which is necessary for metastasis and regions high in VEGF exhibit hyperpermeability(6). Some of the physiological byproducts of angiogenesis regulate the extraction of an agent by a tumor from the blood. This extraction depends on (a) capillary surface area, S, (b) capillary permeability, P, (c) capillary blood flow, F, (d) transit time of the agent through the tumor interstitium, and (e) the plasma half-life, T1/2 DIST(7, 8). By imaging the time evolution of a contrast agent in the lesion, one can model agent extraction. Knowing the plasma half-life of an agent and regional blood flow provides a measure of the capillary surface area and permeability. Such knowledge may provide a means of differentiating benign from malignant tumors.

1. Identifying Tumor Permeability Heterogeneity with MRI Contrast Agents
Michael AREF1, Martin Brechbiel2, Erik WIENER3
1University of Illinois at Urbana-Champaign, University of Illinois at Urbana-Champaign, Department of Nuclear, Plasma and Radiological
Engineering, Urbana, IL USA; 2National Cancer Institute, NIH, Bethesda, MD USA; 3University of Illinois at Urbana-Champaign, Beckman
Institute, Urbana, ILUSA
Introduction measured as function of time. The signal intensity of the blood and a
We tested the hypothesis that macromolecular agents will have a fiduciary (a vial of Gd-DOTA) were also measured for all time points.
greater sensitivity in identifying areas of high regional mammary
tumor permeability-surface area products than low molecular weight Results
agents. New modalities such as ultrasound, MRI, and nuclear Our results agreed with values reported for physiological
medicine may improve breast cancer diagnosis(1). MRI can detect measurements on rats. The experimental values for the low molecular
small tumors, 1 mm, with nearly 100% sensitivity(2) and can weight agent, Gd-DTPA, of the EES volume, plasma volume, and
differentiate benign from malignant tumors with an accuracy of only excretion half-life are Ve = 0.0528 L/kg, Vp = 0.0360 L/kg, and T1/2
30 to 40%(3). A need exists for more accurately characterizing tumor
EXCRE = 25.2 min. For the PAMAM-TU-DTPA G = 4 we found V e =
specificity with MR mammography. Dynamic contrast enhanced MR
0.0251 L/kg, Vp = 0.0344 L/kg, and T1/2 EXCRE = 93.7 min. The
mammography shows promise, and is based on differences in capillary
density. Only a subset of tumor cells acquire angiogenic activity and excretion half-life of the G = 4 derivative falls intermediate of the
this results in heterogeneous capillary density and surface area(4). values obtained for PAMAM-TU-DTPA G = 2 and G = 6
High regional capillary density indicates poor prognosis(5). Tumor derivatives(9). The tumor volume normalized transfer rate between
secreted factors induce angiogenesis, including vascular endothelial plasma and tumor EES, Kp«t/VT, for Gd-DTPA (Table 1) agreed with
growth factor (VEGF), which is necessary for metastasis and regions values reported for other mammary tumors(13, 14). The K p«t/VT for
high in VEGF exhibit hyperpermeability(6). Some of the PAMAM-TU-DTPA G = 4 are less than those of Gd-DTPA, in the
physiological byproducts of angiogenesis regulate the extraction of an same tumor; consistent with the dendrimer agent's larger size.
agent by a tumor from the blood. This extraction depends on (a) (a) (b)
capillary surface area, S, (b) capillary permeability, P, (c) capillary 0.45 0.09
0.08
blood flow, F, (d) transit time of the agent through the tumor 0.4
0.35 0.07
interstitium, and (e) the plasma half-life, T1/2 DIST(7, 8). By imaging 0.3
0.06
0.05
the time evolution of a contrast agent in the lesion, one can model 0.25
0.04
0.2
agent extraction. Knowing the plasma half-life of an agent and 0.15
0.03
regional blood flow provides a measure of the capillary surface area 0.1
0.02
0.01
and permeability. Such knowledge may provide a means of 0.05 0
differentiating benign from malignant tumors. 0
0 10 20 30 40
0 10 20 30 40
Time (min)_ Time (min)_
Methods
Fourth-generation ammonia-core polyamidoamine dendrimers with a Figure 1: Fit of (a) tumor #3 with Gd-DTPA for the whole tumor
DTPA surface (PAMAM-TU-DTPA G = 4, 35,000 MW) were (closed circles) and its ROI (open circles), and (b) tumor #3 with
prepared as described by Wiener et al(9). Gd was complexed by PAMAM-TU-DTPA G = 4 for the whole tumor (closed circles) and its
transmetallation in a citrate buffer, followed by extensive ROI (open circles)
ultrafiltration. To calculate the permeability-surface area products, we Discussion
use a two-compartment model(10) and FLASH image signal intensities The larger agent is less permeable than Gd-DTPA, on the whole
that have been converted to contrast agent concentration data by a tumor, but regions exhibit permeability for the larger agent similar to
standard curve(11): those of the lower molecular weight agent. In tumors #1 and #3
S 1− Χ1 ε −Χ 2 [ΧΑ] regional permeability-surface area products have a greater dynamic
≈ range for the macromolecular agent than for the Gd-DTPA (Figure 1).
S0 1 − Χ1
For Gd-DTPA the Kp«t/VT varies by 29% and 16% between the ROI
Where C1 = e-TR/T10, C2 = TR*r1, TR (sec) is the repetition time, T10 and the whole tumor, while that of the macromolecular agent varies by
(sec) is the longitudinal relaxation time in the absence of contrast 86% and 207%, for tumors #1 and #3 respectively.
agent, and r1 (1/mM*sec) is the longitudinal relaxivity of the agent.
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imaged under anesthesia pre- and post-injection Tumor 1 Kp«t/VT 1/min 0.014 0.0059
of a bolus of Gd-DTPA (0.3 mmoles/kg dose) ve 0.12 0.0098
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2 Kp«t/VT 1/min 0.058 0.0077
Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 2246

2. ve 0.094 0.029 ve 0.098 0.057
3 Kp«t/VT 1/min 0.036 0.015 6 Kp«t/VT 1/min 0.027 0.0066
ve 0.092 0.027 ve 0.092 0.020
3 ROI Kp«t/VT 1/min 0.043 0.046
Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 2246

3. Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 2256