What Are Blood Pool Contrast Media and What Is Their Appeal

Blood pool contrast media (BPCM) are not strictly defined; which compounds should be included within this category may depend upon whom one asks. Yet, a qualitative definition is universally accepted: a blood pool contrast medium for MRI is an enhancing, typically paramagnetic, formulation, that after intravascular administration remains largely in the vascular space for an extended time. For instance, one could choose to define a BPCM as an agent with a plasma half-life of more than 60 min. Typically, such plasma retention would be associated with molecules having molecular weights greater than 50,000 Daltons (VexLer et al. 1994). However, plasma half-life not only varies with molecular weight but also depends on molecular shape and charge, and on the animal species used for the evaluation. Other MRI scientists might wish to include relatively smaller molecules in the category of BPCM and might define "prolonged vas cular retention" as a net plasma half-life greater than that observed for typical small molecular gadolinium contrast media (SMCM) represented by gadopentetate (MW=547 Daltons). For reference, the plasma halflife of gadopentetate in rats is 13 min and approximately 20 min in humans (Weinmann et al. 1984). Using such a broad definition of BPCM would permit inclusion of contrast-enhancing formulations ranging from 5000-50,000 Daltons and larger. Obviously, the pharmacokinetic properties and thus the clinical utility of BPCM could vary substantially across this broad range of molecular sizes. Importantly for the reader, all BPCM should not be considered equivalent or interchangeable. The specific agent and its properties must be considered in any discussion of kinetics, or diagnostic application (see "Appendix").

Appendix

Appendix

Different classes of contrast media (manufacturers and references). 1WEiNmaNN et al. (1984); 2Schering AG, Berlin, Germany (HENdErsoN et al. 2000); 3Amersham Health, Oslo, Norway (Bonk et al. 2000); 4Guerbet, Aulnay-sous-Bois, France (DaldrupLink et al. 2001); 5Epix, Cambridge, MA, USA (Kroft and de Roos 1999); 6Bracco, Milan, Italy (Cavagna et al. 2001); 7Ogan (1988); 8Amersham Health, Oslo, Norway (Hoffmann et al. 2002); 9Okuhata et al. (1999); Weissig et al. (2000)

Different classes of contrast media (manufacturers and references). 1WEiNmaNN et al. (1984); 2Schering AG, Berlin, Germany (HENdErsoN et al. 2000); 3Amersham Health, Oslo, Norway (Bonk et al. 2000); 4Guerbet, Aulnay-sous-Bois, France (DaldrupLink et al. 2001); 5Epix, Cambridge, MA, USA (Kroft and de Roos 1999); 6Bracco, Milan, Italy (Cavagna et al. 2001); 7Ogan (1988); 8Amersham Health, Oslo, Norway (Hoffmann et al. 2002); 9Okuhata et al. (1999); Weissig et al. (2000)

Biological Aspects of Tumor Vessel Hyperpermeability

Although it is commonly taught in biological sciences to "never say never" and conversely, nothing is "always" true, it can be stated with some certainty that tumor microvessels when compared to normal non-tumor vessels are more permeable to the transendothelial diffusion of large molecular solutes. Macromolecular hyperpermeability of tumor vessels has been demonstrated consistently over more than 50 years by numerous, but generally invasive assays; published assays have utilized macromolecular dyes like Evan's blue, radio-labeled proteins such as fibrinogen and albumin, and fluorescent-labeled proteins detected with video microscopy (Genowski and Jain 1986; Nagy et al. 1989; Dvorak 1990; Sevick and Jain 1991; Yuan et al. 1993; Jain 1994). Our group at UCSF first detected and quantitatively monitored by MRI

this macromolecular hyperpermeability of tumors in 1989 when we performed dynamic contrast-enhanced (DCE) MRI in an experimental mouse fibrosarcoma model using a prototype macromolecular contrast agent, albumin-(Gd-DTPA)35 (Aicher et al. 1990). Albumin-(Gd-DTPA)35 is a highly paramagnetic bio-probe with a molecular weight of 92,000 Daltons and a hydrodynamic radius of approximately 6 nm (Ogan 1988). It is interesting to note that even this early attempt to quantitatively assess tumor microvascular permeability previewed the later confirmed potential of the MMCM-enhanced DCE MRI for monitoring tumor response to therapy. This relatively early investigation showed a significant reduction in tumor vessel leakiness, measured by both MRI and Evan's blue assays after only 1-2 h of treatment with tumor necrosis factor-alpha (Aicher et al. 1990). Jain (1994), in an excellent review article appearing in Scientific American, summarized more than a decade of work from his laboratory and from others explaining, from an engineering perspective, the nature of macromolecular diffusion from blood within tumor microvessels into the tumor interstitium. Physiologically, diffusion dominates the transendothelial exchange of macromolecules in the tumor periphery where interstitial pressure is not as high as that often to be found in the tumor core. Jain (1994) notes that within the tumor core, there is an inhibitory effect from high interstitial pressure on the extravascular leakage/diffusion of solutes. This pathophysiological property of tumor hyperpermeability with respect to macromolecular solutes can be exploited by MMCM-enhanced MRI to characterize this consistent biological feature of malignant tumors.

exceptions are found in the microvessels of the brain and the testes; normal vessels in these organs have unusually tight junctions between endothelial cells, limiting diffusion of even SMCM, while tumor vessels in these same organs allow extravascular accumulation of contrast agents.

The degree of transendothelial diffusion for any substance is reflected in its extraction fraction (E) or by the more complex functional parameter termed the 'permeability surface area product' ' (PS) (Renkin 1959; Crone 1963). As implied by the name, the PS parameter depends on both the localized permeability of the vessel and the surface area of the vessel available for transendothelial diffusion. Intuitively, one can appreciate that diffusion of solutes across the endothelium will also depend on the rate of blood flow in the leaky microvessel. One could reasonably predict that with slower flow there would be more time for permeable solute molecules to actually escape the blood compartment and diffuse into the extravascular space.

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