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, P eff, 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. P eff was measured in manually defined regions of interest, corresponding to a whole tumor (ROI WHOLE) or to subregions of a tumor (ROIs SUB). The P eff of the ROI WHOLE 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). P eff decreased with increasing tumor volume in R-18, but was independent of tumor volume in A-07. The intratumor heterogeneity in P eff exceeded the intertumor heterogeneity in both tumor lines. Some ROIs SUB showed P eff values that were similar to or slightly higher than the P eff 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 P eff values, i.e. values that are up to 10-fold higher than those of normal tissues.