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Identifying Tumor Permeability Heterogeneity with MRI Contrast Agents
                                               Micha...
ve                 0.094         0.029              ve                0.098   0.057
 3         Kp«t/VT    1/min   0.036   ...
Proc. Intl. Soc. Mag. Reson. Med 9 (2001)   2256
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Identifying Tumor Permeability Heterogeneity with MRI Contrast Agents

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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.

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Identifying Tumor Permeability Heterogeneity with MRI Contrast Agents

  1. 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. References We examined the differences in regional tumor uptake using the tumor 1. Edell, S. L., et al. (1999) Delaware Medical Journal 71, 377-382. compartment of a two-compartment model: 2. Heywang, S. H., et al. (1989) Radiology 171, 95-103.     3. Orel, S. G., et al. (1994) Radiology 190, 484-493. Κ π↔ τ  αϖ − ατ α2 ϖε − βτ  α1 ϖ α2 ϖ  − ς τ τ  4. Folkman, J. (1994) J Clin Oncol 12, 441-443. [ CA t (t)] = ∆  ε + ε − + ε 1 ε ε ε ςα ςβ  ς α ς β   5. Weidner, N. (1999) J Pathol 189, 297-299. 1− τ 1− τ 1 − τ 1− τ   6. Dvorak, H. F. (1990) in International Symposium on the Effects of Therapy on  Κ π↔τ Κ π ↔τ  Κ π↔τ Κ π↔τ   Biology and Kinetics of the Residual Tumor, Part A; Preclinical Aspects (Wiley- Where a1,2 (kg/L) are the normalized concentration Liss, New York, NY). amplitudes for unit dose, a (1/min) is the 7. Baxter, L. T., et al. (1991) Microvasculature Research . distribution rate constant, b (1/min) is the 8. Jain, R. K. (1990) Cancer and Metastasis Reviews , 253-266. 9. Wiener, E. C., et al. (1994) Magn Reson Med 31, 1-8. excretion rate constant, Kp«t (L/kg*min) represents the 10. Tofts, P. S. (1997) J Magn Reson Imaging 7, 91-101. isodirectional flow rate per unit volume between the plasma and tumor 11. Su, M.-Y., et al. (1994) Magn Reson Med 32, 714-724. EES compartments and ve is the volume fraction of EES in the tumor. 12. Stoica, G., et al. (1983) Am J Pathol 110, 161-169. Female Sprague Dawley rats with N-ethyl-N-nitrosourea (ENU) 13. den Boer, J. A., et al. (1997) J Magn Reson Imaging 7, 702-715. induced mammary tumors(12) were imaged by a multislice FLASH 14. Roberts, T. P. L. (1997) J Magn Reson Imaging 7, 82-90. sequence (Q = 80°, TR = 70 ms, TE = 6 ms, FOV = Table 1 300 mm, slice thickness = 3.0 mm, number of Parameter Units Gd- PAMAM G = slices = 5) at 1.5 Tesla. Each rat was initially DTPA 4 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 followed by PAMAM-TU-DTPA G = 4 dendrimer (0.0576 1 Upper Kp«t/VT 1/min 0.018 0.011 mmoles/kg dose), 24 hours later. Following the injection, regions of ve 0.13 0.017 interest were selected from the tumors and the signal intensity was 2 Kp«t/VT 1/min 0.058 0.0077 Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 2246
  2. 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. 3. Proc. Intl. Soc. Mag. Reson. Med 9 (2001) 2256

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