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Noninvasive Magnetic Resonance Imaging of Transport and Interstitial Fluid Pressure in Ectopic Human Lung Tumors

Departments of ¹ Biological Regulation and ² Veterinary Resources, Weizmann Institute of Science, Rehovot, Israel

Requests for reprints: Hadassa Degani, Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel 76100. Phone: 972-8-9342017; Fax 972-8-936154; E-mail: hadassa.degnani{at}weizmann.ac.il.

Tumor response to blood borne drugs is critically dependent on the efficiency of vascular delivery and transcapillary transfer. However, increased tumor interstitial fluid pressure (IFP) forms a barrier to transcapillary transfer, leading to resistance to drug delivery. We present here a new, noninvasive method which estimates IFP and its spatial distribution in vivo using contrast-enhanced magnetic resonance imaging (MRI). This method was tested in ectopic human non–small-cell lung cancer which exhibited a high IFP of 28 mm Hg and, for comparison, in orthotopic MCF7 human breast tumors which exhibited a lower IFP of 14 mm Hg, both implanted in nude mice. The MRI protocol consisted of slow infusion of the contrast agent [gadolinium-diethylenetriaminepentaacetic acid (GdDTPA)] into the blood for 2 hours, sequential acquisition of images before and during the infusion, and measurements of T₁ relaxation rates before infusion and after blood and tumor GdDTPA concentration reached a steady state. Image analysis yielded parametric images of steady-state tissue GdDTPA concentration with high values of this concentration outside the tumor boundaries, 1 mmol/L, declining in the tumor periphery to 0.5 mmol/L, and then steeply decreasing to low or null values. The distribution of steady-state tissue GdDTPA concentration reflected the distribution of IFP, showing an increase from the rim inward, with a high IFP plateau inside the tumor. The changes outside the borders of the tumors with high IFP were indicative of convective transport through the interstitium. This work presents a noninvasive method for assessing the spatial distribution of tumor IFP and mapping barriers to drug delivery and transport. (Cancer Res 2006; 66(8): 4159-66)

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