The Role of Blood Pool Contrast Media in the Study of Tumor Pathophysiology

Characterizing the biological properties of individual tumors has become a major goal for non-invasive imaging. With growing enthusiasm, the use of serial MRI to monitor the pharmacokinetics of paramagnetic contrast media is being explored to functionally characterize tumors, particularly tumor vascularity. Analysis and kinetic modeling of the dynamic tumor enhancement response after contrast medium administration is being applied to generate quantitative estimates of microvascular characteristics, particularly the fractional blood volume and the microvascular permeability of tumor vessels. Understandably, it is commonly hoped by many MR imagers that the currently available and widely used gadolinium-based contrast media, all belonging in the class of small molecular contrast media (SMCM <1000 Daltons) will be satisfactory for characterization of microvessels with dynamic contrast-enhanced imaging. But it should be emphasized that endothelial permeability to solutes of substantially different size cannot be equated. Unfortunately, SMCM are too small to optimally exploit the well-recognized hyperpermeability of neoplastic microvessels; such hyperpermeability, with rare exception, has been consistently demonstrated in relation to larger macromolecular solutes. Smaller solutes in the size range of commercially available gadolinium chelates are known to diffuse across vascular endothelium in both normal and neoplastic tissues; a notable exception being the blood–brain barrier. Thus, the differentiation of normal from neoplastic tissue by the MRI assay of tissue SMCM leakage is problematic. A macromolecular contrast media (MMCM) is favored to probe and quantitatively estimate by MRI the elevated macromolecular permeability of tumor microvessels. Another obstacle to quantitative MRI tumor characterization pursued with SMCM is the highly variable and unpredictable vascular extraction fraction, both in normal and in neoplastic tumor tissues. MMCM are also referred to as blood pool contrast media (BPCM). While BPCM/MMCM are now being clinically developed and positioned for governmental approval, prototype MMCM are being applied with considerable success in a host of experimental tumor models. The pre-clinical results show strongly positive and signifi cant correlations between MMCMassayed tumor vascular permeability and tumor blood volume with pathologic tumor grade, tumor angiogenesis as assayed by the histologic microvascular density, and with tumor response to multiple forms of anti-angiogenesis therapy. In groups of tumors characterized both by SMCM and MMCMenhanced MRI, the correlations between MRI assays and histopathologic endpoints are consistently superior using the macromolecular-enhanced imaging.