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

The uptake of albumin-Evans blue in human melanoma xenografts was studied a nd 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. Thre e melanoma lines (A-07, R-18, U-25) were included in the study. Tissue conc entrations of albumin-Evans blue were determined by spectrophotometry. The [Rb-86] uptake method was used to measure tumour blood supply. Vascular den sity was determined by stereological analysis of histological sections. Mic rovessel permeability was measured by using the indicator diffusion method. Contrast-enhanced magnetic resonance imaging was used to measure tumour ex tracellular volume fraction. The fractional volume of the extracellular spa ce governed the uptake of albumin-Evans blue in the tumours. The uptake of albumin-Evans blue in the extracellular space was primarily limited by tran sport in the vasculature and not by transport across the microvascular wall or the transport through the interstitium. Our study thus suggests that no vel strategies for improving the delivery of macromolecular therapeutic age nts to tumours should focus on enhancing the tumour blood supply, increasin g the half-life of the therapeutic agent in the blood plasma and/or enhanci ng 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.