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Dynamic Contrast-enhanced MR Imaging Kinetic Parameters and Molecular Weight of Dendritic Contrast Agents in Tumor Angiogenesis in Mice¹

¹ From the Department of Radiology (Q.G.d.L., R.G.H.B.T., J.M.A.v.E., W.H.B.) and Angiogenesis Laboratory, Departments of Pathology and Internal Medicine (A.W.G.), Maastricht University Hospital, P. Debyelaan 25, 6202 AZ Maastricht, the Netherlands; and Laboratory of Macromolecular and Organic Chemistry (S.L., M.H.P.v.G.) and Department of Biomedical Engineering (M.H.P.v.G., J.M.A.v.E., W.H.B.), Eindhoven University of Technology, Eindhoven, the Netherlands. Received March 2, 2004; revision requested May 13; revision received June 4; accepted July 8. Supported in part by the Cardiovascular Research Institute, Maastricht, the Netherlands. Address correspondence to Q.G.d.L. (e-mail: qdlu@rdia.azm.nl).

View larger version (35K): [in a new window]   Figure 1. Schematic presentation of the different generations of poly(propylene imine) dendrimers with the gadolinium diethylenetriaminepentaacetic acid moiety that underwent complexation with gadolinium chloride (insert). The number of gadolinium complexes, from left to right, are one, four, 16, and 64, respectively.

View larger version (19K): [in a new window]   Figure 2a. Graphs of average whole-tumor values show (a) a negative relationship between KPS and molecular weight, (b) a possible positive relationship between reflux rate (k) and molecular weight, and (c) a threshold effect, with marked decrease of fPV between dendritic contrast agents with molecular weights of 3.0 and 12 kDa. The error bars indicate standard errors of the mean and show intertumor variation in the different contrast agent groups. The error bars (standard errors of the mean) show greater intertumor variation in KPS and fPV for low-molecular-weight dendritic contrast agents than for high-molecular-weight contrast agents, whereas the standard error in k values was equivalent for the contrast agents with different molecular weights.

View larger version (18K): [in a new window]   Figure 2b. Graphs of average whole-tumor values show (a) a negative relationship between KPS and molecular weight, (b) a possible positive relationship between reflux rate (k) and molecular weight, and (c) a threshold effect, with marked decrease of fPV between dendritic contrast agents with molecular weights of 3.0 and 12 kDa. The error bars indicate standard errors of the mean and show intertumor variation in the different contrast agent groups. The error bars (standard errors of the mean) show greater intertumor variation in KPS and fPV for low-molecular-weight dendritic contrast agents than for high-molecular-weight contrast agents, whereas the standard error in k values was equivalent for the contrast agents with different molecular weights.

View larger version (18K): [in a new window]   Figure 2c. Graphs of average whole-tumor values show (a) a negative relationship between KPS and molecular weight, (b) a possible positive relationship between reflux rate (k) and molecular weight, and (c) a threshold effect, with marked decrease of fPV between dendritic contrast agents with molecular weights of 3.0 and 12 kDa. The error bars indicate standard errors of the mean and show intertumor variation in the different contrast agent groups. The error bars (standard errors of the mean) show greater intertumor variation in KPS and fPV for low-molecular-weight dendritic contrast agents than for high-molecular-weight contrast agents, whereas the standard error in k values was equivalent for the contrast agents with different molecular weights.

View larger version (27K): [in a new window]   Figure 3. Normalized histograms show that low-molecular-weight contrast agents result in much greater range in spatial distribution (ie, intratumor variation) of the measured KPS values in individual voxels compared with the high-molecular-weight contrast agents. Each interval column represents the tumor values; the black part of the column represents tumor core values, and the gray part represents tumor rim values. Error bars represent the standard error of the mean and show the intertumor variation in the different contrast agent groups. KPS values of 14.5 or more were pooled (*).

View larger version (59K): [in a new window]   Figure 4. Color-coded maps of KPS values measured for the voxels in the central section through the tumor show that use of low-molecular-weight contrast agents results in higher KPS values, particularly in the tumor rim. Gray-scale voxels to the lower and upper right side of each tumor are adjacent tissue of the mouse’s left hind limb; gray-scale voxels within the tumors were rejected from kinetic analyses because of poor enhancement (possible necrotic areas) or excessive fit errors.