Investigating the Vascular Phenotype of Subcutaneously and Orthotopically Propagated PC3 Prostate Cancer Xenografts Using Combined Carbogen Ultrasmall Superparamagnetic Iron Oxide MRI

The aim of this study was to use the combined carbogen-ultrasmall superparamagnetic iron oxide (CUSPIO) magnetic resonance imaging (MRI) method, which uses spatial correlations in independent susceptibility imaging biomarkers, to investigate and compare the impact of tumor size and anatomical site on vascular structure and function in vivo. Mice bearing either subcutaneous or orthotopic PC3 LN3 prostate tumors were imaged at 7 T, using a multi-gradient echo sequence to quantify R(2)(∗), before and during carbogen (95% O(2)/5% CO(2)) breathing, and subsequently following intravenous administration of USPIO particles. Carbogen and USPIO-induced changes in R(2)(∗) were used to inform on hemodynamic vasculature and fractional blood volume (%), respectively. The CUSPIO imaging data were also segmented to identify and assess five categories of R(2)(∗) response. Small and large subcutaneous and orthotopic tumor cohorts all exhibited significantly (P < 0.05) different median baseline R(2)(∗), ΔR(2)(∗)(carbogen), and fractional blood volume. CUSPIO imaging showed that small subcutaneous tumors predominantly exhibited a negative ΔR(2)(∗)(carbogen) followed by a positive ΔR(2)(∗)(USPIO), consistent with a well perfused tumor vasculature. Large subcutaneous tumors exhibited a small positive ΔR(2)(∗)(carbogen) and relatively low fractional blood volume, suggesting less functional vasculature. Orthotopic tumors revealed a large, positive ΔR(2)(∗)(carbogen), consistent with vascular steal, and which may indicate that vascular function is more dependent on site of implantation than tumor size. Regions exhibiting significant ΔR(2)(∗)(carbogen), but no significant ΔR(2)(∗)(USPIO), suggesting transient vascular shutdown over the experimental timecourse, were apparent in all 3 cohorts. CUSPIO imaging can inform on efficient drug delivery via functional vasculature in vivo, and on appropriate tumor model selection for pre-clinical therapy trials