1. ¹Department of Biophysics, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway
2. ²Department of Medical Physics, The Norwegian Radium Hospital, Montebello, N-0310 Oslo, Norway

Correspondence: Dr EK Rofstad, E-mail: e.k.rofstad@labmed.uio.no

Received 31 May 2002; Revised 24 September 2002; Accepted 1 October 2002.

Abstract

Intratumour heterogeneity in the uptake of blood-borne technetium-labelled human serum albumin (^99mTc-HSA) was studied in human melanoma xenografts in an attempt to identify transport barriers leading to inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumours. The Bioscope imaging system, which can detect the distribution of ^99mTc in 10-m-thick tissue sections with a spatial resolution of just above 50 m, was used to image the ^99mTc-HSA uptake. Xenografted tumours of four human melanoma cell lines were included in the study. Significant intratumour heterogeneity in the uptake of ^99mTc-HSA was detected. The heterogeneity had two distinctly different components, one random and one radial component. The uptake was lowest in the centre of the tumours and increased towards the tumour periphery. This radial heterogeneity was superimposed by a random heterogeneity, that is, spots with high uptake colocalised with spots with high vascular density and regions without significant uptake colocalised with necrotic regions. The magnitude of the heterogeneity did not change significantly with time after the administration of ^99mTc-HSA. The tumours showed a random and a radial heterogeneity in blood perfusion similar to that in the uptake of ^99mTc-HSA. The observations reported here suggest that the intratumour heterogeneity in the distribution of ^99mTc-HSA was initiated primarily because of heterogeneity in the supply of ^99mTc-HSA through the microvasculature, and that the presence of severe transport barriers in the tumour interstitium prevented significant equalisation of the initial heterogeneity with time. Consequently, strategies for improving the delivery of macromolecular therapeutic agents to tumours should focus on increasing the tumour blood perfusion to increase the total uptake and improving the diffusion conditions in the tumour interstitium to diminish the heterogeneity in the uptake.