Characterizing gadofosveset for use in quantitative tracer kinetic MRI studies

Quantitative MRI has become a very powerful tool for the assessment of tissue physiology and patho-physiology in vivo. In particular, dynamic contrast-enhanced (DCE) MRI combined with the analysis of tracer kinetics enables the researcher to probe microvascular physiology in a non-invasive and repeatable manner. However, there are few tracers available for such studies and only one small molecule (Gd-DTPA) has been well characterized and is licensed for studies in humans. Studies have been performed using rodent models to assess a variety of larger tracer molecules that provide more specific information about blood volume and microvascular permeability but to date none of these tracers has reached the clinical market. One new tracer that has recently been approved for human studies is of interest. Gadofosveset is a Gd-DTPA-like contrast agent that binds reversibly with human serum albumin (HSA). As such, it behaves much like the larger tracers used in pre-clinical studies remaining in the blood pool for extended periods of time and providing useful contrast for MR angiography. Such behaviour is promising for characterizing microvascular permeability but such measures are complicated by the reversible binding to HSA; i.e. at any given time a fraction of the gadofosveset will be bound and behave like an intravascular tracer while the remaining fraction will be free and behave like Gd-DTPA and distribute more freely. The objective of this study is to characterize gadofosveset and its in vivo kinetics prior to application of the tracer in quantitative DCE-MRI studies. This will be achieved using a series of experiments with the following specific aims: Exp. 1 - to characterize the relaxivity of gadofosveset. Experiments will be performed in vitro to establish the relaxivity of gadofosveset at a range of field strengths (1.5 T, 3 T, 4.7 T & 9.4 T) in human and mouse serum albumin. By escalating the gadfosveset concentration the relaxivity of bound and free tracer and exchange rate between these states may be determined. The effect of pH will also be assessed since this may change in pathology. Exp. 2 - to measure the vascular concentration of gadofosveset as a function of time following intravenous injection in mice (determination of the arterial input function (AIF)). This will be performed according to Port et al. (Investigative Radiology 40:565-573, 2005) using inductively coupled plasma mass spectroscopy to establish the absolute concentration of gadofosveset and building upon the work in exp. 1. These results will enable us to assess vascular concentration from T1 measurements performed in vivo. Exp. 3 - to assess gadofosveset kinetics in vivo. Imaging studies will be performed in mice to assess uptake in tissues such as muscle and tumour. Tumour models with known differences in vessel density and microvascular permeability will be employed to test the ability of gadofosveset enhanced MRI to differentiate between them. Comparisons will be made, in the same animals, with Gd-DTPA enhanced MRI. The results will be correlated with histological measures of vessel density and estimates of perfusion obtained using Hoeschst 33542 staining. Exp. 4 - to model the tracer kinetics and apply to human studies. The results of these studies will aid the development of extended tracer kinetics models to account for the reversible binding of gadofosveset and the variation of effect with field strength. These models will be tested using data obtained from clinical/volunteer studies performed in humans. These experiments and the interactions with colleagues helping to run them will provide the student with a broad, interdisciplinary training. In addition to mathematical modelling and data analysis the student will gain experience with in vivo MRI using a range of systems and field strengths (phantom preparation and animal monitoring), ICP-MS (sample preparation and processing) and human imaging studies.