Dissertation Defense: Trevor Lyons
Candidate: Trevor Lyons
Major: Chemistry
Advisor: Sarah L. Stoll, Ph.D.
Title: Parameters Dictating Behavior of Cluster-Nanocarrier Magnetic Resonance Imaging Contrast Agents
Magnetic Resonance Imaging (MRI) is one of the most powerful diagnostic imaging modalities available to researchers and diagnosticians, utilizing magnetic field gradients to create 2- and 3-dimensional images of soft tissue without the need for harmful radiation. While MRI is used over 40 million times annually and for many diagnostic purposes, natural contrast provided by soft tissue is adequate, in about a third of uses, an exogenous contrast agent is administered, often in imaging of the brain, spinal cord, and in angiography. These contrast agents, generally consisting of highly paramagnetic gadolinium chelates, function by enhancing the rate of longitudinal (T1) and transverse (T2) relaxation of surrounding protons, resulting in enhanced contrast in imaging. Multiple classes of contrast agents exist such as paramagnetic agents, chemical exchange saturation transfer, and direct detection, but gadolinium chelates remain the
clinical “gold standard”.
While gadolinium chelates provide sufficient contrast for diagnosis of ailments, this class of contrast agents cannot be administered to patients with renal dysfunction as they can result in a fatal fibrosis of the skin and organs known as nephrogenic systemic fibrosis. Furthermore, in healthy patients who undergo numerous administrations, accumulation in the brain and bone has been more recently investigated as an area of concern so there is a pressing need for biogenic alternatives in the form of iron (III) or manganese (II). Our group has investigated manganese and iron-based metal-oxo clusters, which exhibit high relaxivities, as alternatives to gadolinium chelates. These metal-oxo clusters exhibit varying degrees of solution stability and relaxivity and have been understudied mechanistically in terms of their behavior as MRI contrast agents, in comparison to chelates for which behavior as contrast agents is well understood. Among a number of metal-oxo clusters, two have been selected as systems for further in-depth mechanistic study,
Mn8Fe4O12(O2CCH3)16(H2O)4, or Mn8Fe4, and Mn3(O2CCH3)6(Bpy)2, or Mn3Bpy. Mn8Fe4 exhibits a per metal r1 of 2.3 mM-1s-1 and an outstanding per iron relaxivity of 6.9 mM-1s-1 whereas Mn3Bpy exhibits a very high r1 of 6.9 mM-1s-1.
The parameters dictating high relaxivity in these clusters in accordance with Solomon Bloembergen Morgan theory were thoroughly examined to translate the methods used in the chelate contrast community to metal-oxo clusters. The water exchange dynamics of these clusters were examined spectroscopically via variable temperature 17O and 1H NMR. Rotational dynamics of the cluster, Mn8Fe4 were assessed via the Debye Stokes equation, and the solution chemistry of both clusters were closely examined for speciation or hydrolysis as it pertains to contrast agent behavior. Their associated nanoparticle conjugates were also examined mechanistically as contrast agents but also in terms of stability to develop a further understanding of the cluster-nanocarrier relationship to develop further, stable, and efficiently relaxing contrast agents of this class. Finally, we develop initial methods to functionalize the surfaces of the cluster nanocarriers, Mn8Fe4coPS and Mn3BpyPAm to use these nanomaterials as targeted MRI contrast agents or to use them to study more fundamental nano-bio interactions.