Microvascular permeability to macromolecules in human melanoma xenografts assessed by contrast-enhanced MRI—intertumor and intratumor heterogeneity

Several novel macromolecular anticancer agents have fallen short of expectations owing to inadequate and heterogeneous uptake in tumor tissue. In the present work, contrast-enhanced magnetic resonance imaging was used to measure the intertumor and intratumor heterogeneity in the effective microvascular permeability constant, Peff, of an 82 kDa macromolecule in an attempt to identify possible causes of the inadequate and heterogeneous uptake. Tumors of two human melanoma xenograft lines (A-07 and R-18) were included in the study. Human serum albumin with 30 gadopentetate dimeglumine units per molecule was used as a model molecule of macromolecular therapeutic agents. Peff was measured in manually defined regions of interest, corresponding to a whole tumor (ROIWHOLE) or to subregions of a tumor (ROIsSUB). The Peff of the ROIWHOLE of individual tumors ranged from 1.4 × 10−7 cm/s to 2.8 × 10−7 cm/s (A-07) and from 7.7 × 10−8 cm/s to 3.2 × 10−7 cm/s (R-18). Peff decreased with increasing tumor volume in R-18, but was independent of tumor volume in A-07. The intratumor heterogeneity in Peff exceeded the intertumor heterogeneity in both tumor lines. Some ROIsSUB showed Peff values that were similar to or slightly higher than the Peff values of albumin in normal tissues. Our observations suggest that inadequate and heterogeneous uptake of macromolecular therapeutic agents in tumor tissue is partly a result of low and heterogeneous microvascular permeability. However, the microvascular wall is probably not the major transport barrier to macromolecules in A-07 and R-18 tumors, as most individual tumors and individual tumor subregions showed high Peff values, i.e. values that are up to 10-fold higher than those of normal tissues.