Macromolecule uptake in human melanoma xenografts:: relationships to blood supply, vascular density, microvessel permeability and extracellular volume fraction

The uptake of albumin-Evans blue in human melanoma xenografts was studied and related to blood supply, vascular density, microvessel permeability and extracellular volume fraction in an attempt to identify transport barriers limiting the delivery of macromolecular therapeutic agents to tumours. Three melanoma lines (A-07, R-18, U-25) were included in the study. Tissue concentrations of albumin-Evans blue were determined by spectrophotometry. The [Rb-86] uptake method was used to measure tumour blood supply. Vascular density was determined by stereological analysis of histological sections. Microvessel permeability was measured by using the indicator diffusion method. Contrast-enhanced magnetic resonance imaging was used to measure tumour extracellular volume fraction. The fractional volume of the extracellular space governed the uptake of albumin-Evans blue in the tumours. The uptake of albumin-Evans blue in the extracellular space was primarily limited by transport in the vasculature and not by transport across the microvascular wall or the transport through the interstitium. Our study thus suggests that novel strategies for improving the delivery of macromolecular therapeutic agents to tumours should focus on enhancing the tumour blood supply, increasing the half-life of the therapeutic agent in the blood plasma and/or enhancing the volume of the extracellular space available to macromolecules rather than on increasing the permeability of the microvascular wall or improving diffusion conditions in the tumour interstitium. (C) 2000 Elsevier Science Ltd. All rights reserved.