Intratumour heterogeneity in the uptake of macromolecular therapeutic agents in human melanoma xenografts

Abstract

Intratumour heterogeneity in the uptake of blood-borne technetium-labelled human serum albumin ( 99m Tc-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 99m Tc in 10-mmthick tissue sections with a spatial resolution of just above 50 mm, was used to image the 99m Tc-HSA uptake. Xenografted tumours of four human melanoma cell lines were included in the study. Significant intratumour heterogeneity in the uptake of 99m Tc-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 99m Tc-HSA. The tumours showed a random and a radial heterogeneity in blood perfusion similar to that in the uptake of 99m Tc-HSA. The observations reported here suggest that the intratumour heterogeneity in the distribution of 99m Tc-HSA was initiated primarily because of heterogeneity in the supply of 99m Tc-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.

Spatial and temporal mapping of heterogeneity in liposome uptake and microvascular distribution in an orthotopic tumor xenograft model

“…It is recognized that MVD alone may not constitute a sufficient cause for increased accumulation [65]; nevertheless, the greater number of vessels per area provides an increased probability that more of those vessels will be patent and able to deliver liposomes. Increased uptake of macromolecular and nano-based agents in areas of high tumor vascular density has indeed been reported [13,66,67]. Finally, a time-dependent penetration of liposomes was observed, as significantly greater distances were achieved over time in each region.…”

Changes in intratumor heterogeneity in blood perfusion in intradermal human melanoma xenografts during tumor growth assessed by DCE-MRI

“…In previous studies, significant intertumor heterogeneity in mean blood perfusion has been measured in A-07 tumors by global DCE-MRI [19] and by using the [ 86 Rb] uptake method [20]. Regional measurements of the blood perfusion in A-07 tumors by DCE-MRI [21] and by using a radioactive tracer [22] have shown also that the intratumor heterogeneity is significant. A systematic heterogeneity was discovered, as the blood perfusion was found to be higher in the tumor periphery than in central tumor regions [22].…”

Radiation Improves the Distribution and Uptake of Liposomal Doxorubicin (Caelyx) in Human Osteosarcoma Xenografts

“…In our OHS xenograft model growing s.c., we also have demonstrated a high IFP in the interior of the tumor and a steep pressure gradient in the periphery. 7 Another explanation for the increased doxorubicin uptake in the tumor periphery could be the higher vascular density in this area compared with in central parts of the tumor (31). Liposomal accumulation has been reported to correlate with vascular density (10).…”