Developing Contrast Agents for High Field Magnetic Resonance Imaging (MRI)
This part of our research effort aims to find ways to make contrast agents more effective in order to drive down detection limits and open up the possibility of molecular imaging (imaging molecular processes) by MRI. There are two basic challenges to this goal: 1) How to drive down detection limits (i.e. how to make the contrast agent more effective); 2) How to achieved this at the high magnetic field strengths increasingly used by MRI.
Optimizing Contrast Agent Properties for High Field Applications
We apply classical and novel coordination chemistry techniques to tuning the physical properties of paramagnetic chelates for high field MRI applications. We use as the basis for our research the clinical contrast agent GdDOTA. We then make modifications to the structure of the chelate in order to control coordination chemmistry. This work involves organic synthetic methodology. We then examine how the changes we have made affect the properties of the chelate through physical-inorganic methods. Of particular interest are parameters such as water exchange kinetics, chelate stability and inertness, electron spin relaxation and relaxivity (ther effectiveness of the chelate as a contrast agent). However, we also study luminescent and NMR properties of the chelates to understand both structural and dynamic considerations of the chelate. By exploring these parameters we can develop a picture of how a contrast agent can be optimized for optimum performance at high field. Of particular interest is controlling the rate of water exchange, which at high field must be very fast. However, we have recently discovered that the extremely fast water exchange kinetics traditionally thought necessary for optimal high field performance have a negative impact on chelate hydration and therefore relaxivity. The optimum water exchange is therefore somewhat slower and the search for the optimal water exchange rate continues.
Related Publications
B.C. Webber, C. Cassino, M. Botta, and M. Woods, Inorg. Chem., (2015), 54, 2085–2087.
O.M. Evbuomwan, J. Lee, M. Woods, and A.D. Sherry, Inorg. Chem., 2014, 53, 10012–10014.
J.R. Slack and M. Woods, J. Biol. Inorg. Chem., 2014, 19,173–189.
B.C. Webber and M. Woods, Dalton Trans., 2014, 43, 251–258.
S. Avedano, M. Botta, J. Haigh, D. Longo and M. Woods, Inorg. Chem., 2013, 52, 8436-8450.
New Modalities for Contrast Agent Delivery
In addition to improving the function of an individual Gd3+ chelates as an MRI contrast agent we are also pursuing routes that will allow a multitude of Gd3+ chelates to be incorporated into a single MRI contrast agent. To accomplish this goal we are taking a different route than other groups. Macromolecular contrast agents incorporating multiple paramagnetic chelates have typically been prepared by modifying the ligand structure in complex and expensive ways that allow the chelate to be attached to a macromolecular framework. Our approach is radically different, we take simple unmodified chelates and use electrostatically driven aggregation processes to load nanoscale capsule is with paramagnetic complexes. The encapsulation process is completed by formation of our water permeable cell around the chelate aggregate. This approach has proven to be remarkably effective. Capsules can be produced that incorporates many thousands of Gd3+ chelates within a biocompatible and water permeable silica nanoparticle shell. Because the molecular tumbling of the Gd3+ chelate is strongly coupled to that of the nano-capsule's structure, the relaxivity of each chelate is very high. When the relaxivities of each of the many thousands of Gd3+ chelates are summed in a single imaging agent the result is an extremely effective MRI contrast agent.
Related Publications
A. Farashishiko, K.N. Chacón, NJ. Blackburn and M. Woods, Contrast Media and Molecular Imag., (2016), 11, 154–159.
S.E. Plush, M. Woods, Y. Zhou, S.B. Kadali, M.S. Wong, A.D. Sherry, J. Am. Chem. Soc., 2009, 131, 15918–15923.
The Development of New Acquisition Strategies for High Field CE-MRI
To maximise the utility of contrast agents in MRI exams at high field new strategies are required. The effectiveness of gadolinium based MRI contrast agents decreases as the magnetic field strength increases. This decrease in relaxivity is, to some extent, offset by an increase in the intrinsic T1 of tissue as the magnetic field strength is increased. However, the intrinsic spin physics of MRI contrast agents mean that it is very difficult to design a contrast agents that is more effective than current clinical agents at some of the higher magnetic field strengths used in MRI. For this reason our group is exploring new strategies for acquiring imaging data in Contrast Enhanced MRI at high fields.