Transvascular and interstitial transport of a 19 kDa linear molecule in human melanoma xenografts measured by contrast-enhanced magnetic resonance imaging

Cancer therapy involving blood-borne macromolecular therapeutic agents often fails, owing to inadequate macromolecule uptake in malignant tissue. The transvascular and interstitial transport of a 19 kDa linear molecule (NC22181 or poly-[Gd-DTPA]-co-[1,6-diaminohexane]) was studied in the present work in an attempt to identify transport barriers limiting the delivery of macromolecules to tumors. Tumors of four human melanoma xenograft lines were included in the study. The uptake of NC22181 was measured by spoiled gradient recalled magnetic resonance imaging (MRI). The effective microvascular permeability constant and the interstitial influx constant of NC22181 were calculated from NC22181 uptake curves by using a three-compartment tissue model. The uptake of NC22181 was limited by the interstitial transport and not by the transvascular transport in all xenograft lines. If the melanoma xenografts used in this study are representative models of human cancer, our results suggest that strategies for increasing the delivery of macromolecular therapeutic agents to tumors should focus on improving the transport conditions in the interstitium, rather than enhancing the permeability of the microvascular wall. (C) 2001 Wiley-Liss, Inc.