title: Noninvasive magnetic resonance imaging of transport and interstitial fluid pressure in ectopic human lung tumors.
abstract: 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 approximately 28 mm Hg and, for comparison, in orthotopic MCF7 human breast tumors which exhibited a lower IFP of approximately 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 approximately 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, approximately 1 mmol/L, declining in the tumor periphery to approximately 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.
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Hassid
authors.forename: Edna
authors.initials: E
authors.lastname: Furman-Haran
authors.forename: Raanan
authors.initials: R
authors.lastname: Margalit
authors.forename: Raya
authors.initials: R
authors.lastname: Eilam
authors.forename: Hadassa
authors.initials: H
authors.lastname: Degani
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology*; D003287:Contrast Media / Q000493:pharmacokinetics; D045604:Extracellular Fluid / Q000378:metabolism; D019786:Gadolinium DTPA / Q000493:pharmacokinetics; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude
chemical_list: D003287:Contrast Media; D019786:Gadolinium DTPA